MEMORANDUM

rw, TO :

DEPARTMENT

OF HEALTH,
PUBLIC FOOD AND DRUG

EDUCATION,
SERVICE ADMINISTRATION

AND WELFARE

HEALTH

Administrative Hearing Clerk's

Proceedings Staff Office (HFA-305)

DATE:

lj&

3

&tjC

FROM

:

Director Division

of OTC Drug Evaluation

(HFD-510) for

SUBJECT:

Public Administrative File for Anorectal Drug Products Over-the-Counter Human Use Docket No. 80N-0050

In a notice published in the FEDERAL REGISTER on September 26, 1980 the administrative record for anorectal drug products for over-the-counter human use was reopened to allow for consideration of recommendations on camphor-containing drug products that have been received from the Advisory Review Panel on OTC Miscellaneous External Drug Products.

l

Under cover of this memorandum, we are forwarding the volume comprising the Public Administrative File for this statement of the Advisory Review Panel on OTC Miscellaneous External Drug Products concerning OTC drug This volume is to be placed products containing camphor. on public display under docket number 80N-0050. the contact If there are any questions, is Michael Benson at extension 31430. person on my staff

William Attachment

hJ+$“i?
E. Gil ertson,

Pharm.

D.

4

Anorcctal

Drug Products

for Decket

Over-the-Couater No. SON-00:50

Human Use

_Coritcnts 1.0 References 1.1 Call for Data 1.2 List of Panel Members 2nd Liaisons 1.3 Index to Panel Submissions 1.4 Surmary Minutes of Panel Meetings

receive

on thic working draft writh the inspection at the

do not wish to make dis.;jbili proposed regulations will oonsibilities of the Secrcta

-

istrative

requireme s the Social Set

Services

has appro

eterminations Dsled: September 12.19 William J. Driver,
Commissioner
~FRm-FiledQ-~a4 BIUJNC CODE 4llM7-M

es. At the same

of Social Se

20 CFA Parts
Disability Security

404 and 416

e2OCIRThe
Insurance Income and S

doc:llmc*nt. b;lscDd on the rc,Lornmc:ndntiuns.of the Ad\ri\ory Rcvictw Panel on OTC Miscellaneous External Drug Products and the Advisory Review Panel on OTC Topical Analgesic, Antirheumatic, Otic, Bum, and Sunburn Prevention and Treatment Drug Products, is part of the ongoing review of~OTC drug products conducted by the FDA. The agency, having reviewed the Panels’ reports, has determined that any drug product labeled as “camphorated oil” or -“camphor liniment” or any drug product containing camphor in excess of 11 percent is misbranded and is a new drug for which an approved new drug application is required for marketing. The agency has also decided that action to remove camphorated oil dn.$ products and any drug product containing camphor in excess of 11 percent from the mhrket should be ’ implemented expeditiously and not await the full procedural review that has been established for OTC d;ug products. DATE Comments by November 25,196O. ADDRESS: Written comments to the . Hearing Clerk (HFA-305). Food and Drug Administration, Rm. 4-62.5600 Fishers Lane, Rockville. MD 20857.
FOR FURTHER INFORMATION CONTACC:

Social Security A

ation,

William E. Gilbertson, Bureau ofpruge -510). Food and Drug Administration, 5600 Fishers Lane, Rockville. MD 20657,3Ul-4434960.
SUPPLEMENTARY INFORMATIOH: hl

SUMMARY:

The

Social

Administration

plans

ao-29844 F&d BUJNG CODE 4liMl7-M

Q-22-&% 845 am]

m

Food

and Drug

Administration

_b

21 CFR Part 310’

is now

cam

Federal Govemm agreements betwe Administration an

e Social Securi

Camphorated Oil and CamphorContaining Drug Products for Overthe-Counter Human Use; Notice of Proposed Rulemaking ’
AGENCY: ~CTIOH:

1, disability determinations mpliance with State agencies in regulations conta’ ’ g performance dards and othe administrative 8 ements and procedures relating to ability determination function. es will have the option of turning the * func!ion over to the Federal Government

Food and Drug Administration. Proposed rule. -

\ SUMMARY: The Food and Drug Administration (FDA) proposes that drug products labeled as “camphorated oil” or “camphor liniment” and drug products containing camphor in excess of 11 percent be classified in Category II as not generally recognized as safe and effective and as misbranded. This

accordance with Part 330 (21 CFR Part 330). FDA received on March 7.1960. a report of the Advisory Review Panel on OTC Miscellaneous External Drug Products. Under 8 330.10[a)(6) (21 CFR 330.10[a)(6)). the agency issues (1) a proposed regulation containing the monograph recommknded by the Panel, which establishes conditions under which OTC drugs are generally recognized as safe and effective and not . misbranded (i.e., Category I); (2) a statement of the conditions excluded from the monograph because the Panel determined that they would result in the drugs not being generally recognized as safe and effective or would result in misbranding [i.e., Category II); (3) a statement of the conditions excluded. from the monograph because the Panel * determined that the available data are insufficient to classify such conditions under either (1) or (2) above (i.e.. Category III); and (4) the conclusions and recommendations of the Panel. Because the Panel’ recommendations s on camphorated oil contain no Category I or Category III conditions, FDA is issuing a notice, containing the Panel’ s recommendations, which proposes

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such approved nc\v drug application producls in interslate commerce after The Panel’ report has been prepared s the effective dale of this regulation will dependently of FDA, and represents be subject to regulatory action. mebest scientific judgment of the Panel Although the Miscellaneous External al members. Because the Panel strongly Panel’ report was concerned only with s recommended that FDA act swiftly to camphorated oil drug products, the remove camphoratedbil from the. Panel noted that the Advisory Review \ market, the agency has reviewed the Panel on OTC Topical Analgesic, Panel’ report et this time. The Panel s Antirheumatic, Olic, Bum, and Sunburn concluded, and FDA concurs, that Prevention and Treatment Drug ’ camphorated oil is not generally Products (hereinafter referred to as the recognized as safe for OTC use because Topical Analgesic Panel) discussed the of the largk number of harmful I safety of camphor in its report on , accidental ingestions of camphorated external analgesic drug products oil,.often mistaken for castor oil, cod published in the Federal Register on liver oil, mineral oil, olive oil, cough December 4,1979 (44 FR 69788). That medicine, or other products. Moreover, Panel concluded that camphor as an ’ because the risk of poisoning in infants ingredient was safe and effective foruse and young children upon accidental in OTC drug products as a topical ingestion greatly outweighs any ’ analgesic. anesthetic, and antipruritic in questionable benefits to be derived from a concentration of 0.1 to 3.0 percent and the medicinal use of this drug, the as a topical counterirritant in a 3- to llagency has determined that marketing percent concentration. of any camphorated oil drug products The agency has reviewed the Topical should cease.‘ * AnaIgesic Panel’ recommendations s Historically, camphorated oil has concerning camphor. Because of the been a recognized synonym for camphor potential toxicity problems which the liniment. Camphor liniment, which was Miscellaneous External Panel has officially recognized in the National identified, the agency has determined at Formulary (NF), was deleted from the this time that no product coritaining official compendia with publication of camphor in excess of 11 percent can be XIJI (September 1.1970). generally recognized as safe for OTC amphorated oil” or “camphor use. Moreover, because of the risk ofiment.” or any similar name such as . -aE L poisoning in infants and young children “camphor oil” or “camphorated upon accidental ingestion, the agency liniment,” as previously recognized in has determined that marketing of any the official NF and as presently drug prodtict containing camphor in formulated, is a solution of 20 percent excess of 11 percent should cease. The camphor in cottonseed oil. Although no agency. therefore, is also proposing that longer recognized in an official any drug product containing camphor in compendia. the product continues to be excess of 11 percent offered for any use marketed under both names. -in interstate commerce after the The agency has determined that any effective date of the final regulation is drug product labeled as “camphorated misbranded under section 502 of the oil” or “camphor liniment.” or any Federal Food. Drug, and Cosmetic Act similar name such as “camphor oil” or ’ (2l U.S.C. 352) and is a new drug witbin “camphorated liGment” represents a the meaning of section 231(p) of the act potential health hazard because of the possibility of accidental ingestion and .I for which an approved new drug application under section 505 of the act subsequent toxic effects. (21 USC. 355) and Part 314 of the . The agency, therefore, is proposing regulations (21 CFR Part 314) is required that any drug product containing for marketing. In tbe absence of an . camphor which is labeled as approved new drug application such “camphorated oil” or “camphor products in interstate commerce after ’ liniment” or any similar name such as the effective date of this regulation will “camphor oil” or “camphorated .,I be subject to regulatory action. liniment,” and which is offered for any The agency advises that the Topical use in interstate commerce after the Analgesic Panel’ recommendations s on effective date of this regulation is drug products other than those either misbranded-under section 502 of the containing camphor and labeled as Federal Food, Drug, and Cosmetic Act “camphorated oil” or “camphor (21 USC. 352) and is a new drug within linimenf” or any similar name such &I the meaning of section 201(p) of the act “camphor oil” or “camphorated or which an approved new drug . liniment,” or containing camphor in plication under section 505 of the act excess of 11 percent are not affected by 1 USC 355) and Part 314 of the a regulations (21 CFR Part 314) is required this proposed rule. The ‘ . recommendations of the Topicalfor marketing. In the absence of art / .

Category

I1

c;jmphoraled

Cli4ssifiCl3fiOn oil.

AnalgcBsic Panel on camphor and the safety and rsfft:clivenc*ss of products containing camphor in conwnlretione less than II percent will be addressed in the rulemaking proceeding for external analgesic drug products. Elsewhere in this issue bf Ihe Federal Register, the agency has published B notice reopening the administrative record for OTC external analgesic drug products to consider the Miscellaneous External Panel’ recommendation. s TWO other OTC advisory review panels--the Advisory Review Panel on OTC Hemorrhoidal Drug Products and the -I Advisory Review Panel on OTC Cold, Cough, Allergy, Bronchodilator. and Antiasthmatic Drug Products-also . r’ reviewed the safety and effectiveness of camphor. Elsewhere in this issue of the Federal Register, the agency has published notices reopening the . administrative record for OTC anorectal drug products and for OTC cold, cough, I ‘ allergy, bronchodilator, and antiasthmatic drug products to consider the Miscellaneous External Panel’ s recommendation. By the action proposed in this document, the agency does not wish to give the impression that it has made a c fmal determination tha! 11 percent is the upper safe limit for camphor-containing products for OTC use. This determination will be made at a later- .‘ .: date in a future issue of the Federal I. Register. The agency has determined that -. action to remove all camphorated oil 1:. drug products and all drug products containing camphor in excess df 11 .I ’ percent from the market should be I .> implemented expeditiously. Accordingly, the agency advises thai it will cot follow the full OTC rulemaking procedure set forth in $ 330.10 (21 CFR 330.10). FDA will not publish a tentative final order, but will publish a final order sbon after the receipt and consideration of comments on this proposal. It is the agency’ intention that the final order s will become effective upon publication in the Federal Register. Interested Y persons have until November 25.1980 to submit comments on this proposal. Upon the effective date of the _regulation, because of the risk associated with use of camphorated‘ oil drug products and drug prodticts containing camphor in excess of 11 . percent, the agency will request firms to recall to the retail level all drug products containing camphor which purport to be . or are representd as camphorated oil or camphor liniment and all +-ug products’ containing camphor in excess of 11 percent. In the interim manufacturers . are requested voluntarily to discontinue’ marketing of these products. Any

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f.rcturer wishing to asctjrtain \er its product purports to be or is entcd as camphorated oil or ,,hor liniment should submit the IUCI’ formulation and labeling to the S sron of Drug Labeling Compliance, d and Drug Administration, 5800 _ lers Lane, Rockville, MD 20857. he products affected by the proposed iron pose an unwarranted risk of rm, in the agency’ judgment, because s me or all of the following factors are und in these products: a high 3ncentration of a potentially toxic igredient; little or no data to show that he mgredienl at these concentration evels has any benefit or any benefit commensurate with the risk; a name or appearance that confusingly suggests a product intended for ingestion: and a number.of repo?ted incidents of accidental ingestion and harm. Thus, it is particularly important to take action with respect to products with high concentrations of camphor because in these products the ingestion of even a small quantity of the drug poses a serious risk. A proposed review of the safety,. effectiveness, and labeling of all OTC by independent advisory review s was announced in the Federal ter of january 5.1972 (37 e 85). . , d e final regulations providing for this OTC drug review under 0 339.ld.ivere published and made effective in the .. Federal Register of May 11,1972 (37 FR 9464). In accordance 4th these iegulations a request for data and information on &I active ingredients used in OTC miscellaneous external drug products was issued in the Federal Regisfer of November 16.1973 (38 FR 31697). In the Federal Register of August 27.1975 (40 FR 38179). a further notice supplemented the initial notice with a detailed list of ingredients. However, camphorated oil - was not specifically included in either notice. 1 The Commissioner appointed the following Panel to review the information submitted and to prepare a report under 8 330.16(a)(l) and (5) on the safety, effectiveness,‘ and labeling of the ingredients in those products: William E. Lo~terhos. M.D., Chairman . Rose Dagirmanjian, Ph.D. Vincent 1. Derbes. MD. (resigned July 1978) George C. Cypress, M.D. (resigned November * 1976) , Yelva L Lynfield. M.D. (appointed October E. Morton. SC D. N. O’ Donbghue. M.D. Thester L Rossi. D.Pk J. Robert Hewson M.D. [appointed September 1978)

’ . .

Rcpr~*sentntivcs of ccinjumer and industry interests served as nonvoting members of the Panel. Marvin M. Lipman. M.D., norninated by Consumers Union, served as the consumer liaison, Gavin Hildick-Smith. M.D., served as industry liaison from January until August ‘ 1975. followed by Bruce SemPle, M.D., until February 1970. Both were nominated by the Proprietary Association. Saul A. Bell, Pharm. D., nominated by the Cosmetic, Toiletry, and Fragrance Association, also served as an industry liaison since June 1975. Two nonvoting consultants, Albert A. Belmonte, Ph. D. and Jon j. Tanja. R.Ph.. M.S., have provided assistance to the Panel since February 1977. The fo!lowiQ FDA employees assisted the Pa&i: John M. Davitt served as Executive Secretary until August 1977. followed by Arthur Auer until September 1978, followed by John T. McElroy. J.D. Thomas D. DeCillis, R.Ph.. served as Panel Administrator until April 1976, followed by Michael D.Kennedy until January 1978. followed by John T. McElroy, J.D. Joseph Hussion, R.Ph., served as Drug Information Analyst until April 1976, followed by Victor H. Lindmark, Pharm. D.. until March 1978, followed by Thomas J. McGinnis. R.Ph. The Advisory Review Panel on OTC Miscellaneous External Drug Products was charged with the review of many categories of drugs, but due to the large number of ingredients and varied labeling claims.-the Panel decided to . review and publish its findings separately for several drug categories and individual drirg products. The Panel presents its conclusiorts and recommendations for camphorated oil in this document The review of other categories of miscellaneous external drug products wilI be continued by the PaneLand its fmdings will be published’ in future issues of the Federal Regisfer as the.Panel completes its deliberations _.. on each category of drugs. The Panel was first convened on January 13.1975 in an organizational meeting. Working meetings which dealt with the topic of this document were held on January 14 and 15, February 27 and 28,1977; October 29 and 30.1978; January 27 and 28, and March 7.1980. The minutes of the Panel meetings are on public display in the Hearing Clerk’ s Office (HFA-395). Food and Drug Administration (address given above). No submissions were m?rde for camphorated oil. However, camphorated oil came to the attention of the Panel By Mr. Carmine Varano, a New Jersey pharmacist, who reported a number of accidental ingestions of camphorated oil to FDA. In many of -

these CRSCS.con<umcrs hi+d rnist;tkcn cdmphoratl:d oil for castor oil or code liver oil (Ref. 1). At the Panel’ request. Mr. Varano s appeared before the Panel at its January 28. 1986 meeting to provide information and to express his views on camphorated oil. (See Sufefy below.) No other person requested an opportunity to appear before the Panel on this / subject; however, the American Pharmaceutical Association filed a written statement on camphorated oil with the Panel recommending that the .Panel classify camphorated oil as Category II for both safety and effectiveness (Ref. 2). The Panel has thoroughly reviewed the literature and considered all pertinent data and information through March 7.1986 in arriving at its conclusions and recommendations on camphorated oil.’ . In accordance with the OTC dn$ : review regulations (27 CFR 330.10) the ‘ I Panel considered camphorated oil with respect to the following three categories: Category I. Conditions under which camphorated oil is generally recognized as safe and effective and is not - misbranded. Category II. Conditions under which . camphorated oil is not generally recognized as safe and effective or is misbranded. Category III. Conditions for which the available data are insufficient to permit final classification at this time. The Panel concludes that’ camphorated oil is not safe (Category II) for any OTC external use. Camphorated Oil . . Camphorated oil. also known as camphor Bniment, is a simple solution of 20 percent camphor in cottonseed oil. It was officially recognized in the fIrat edition of ‘ The United States Pharmacopeia,” published in 1820. Itbas been used mainly in the past as a counterirritant. nrbefacient, and liniment for treating sprains, bruises, rheumatism, and other inflammatory conditions. Historically, camphorated oil has been the official synonym for camphor liniment when camphor liniment was recognized in the official NF. It remained the officially recognizedsynonym in NF XI (October 1.1980). but was deleted as the officially recognized synonym in NF XII (September 1.19~). Ultimately, camphor liniment was.. deleted from the official compendia with publication of NF XIII (Septembefl. 1970). Although no longer recognized in an official compendia, the product continues to be marketed under both names and has fallen into disuse to some degree in recent ye=.

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neither has developed the process OF glucuronidation and. therefore, cannot detoxify camphor (Ref. 13) Camphor has been shown to pass through the placenta and hH8 been implicated in the deaths of newborn infants (Ref. 14). In one case a newborn infant died 30 minutes after delivery when the mother ’ had ingested compahorated oil 36 hours before giving birth. Camphor was . detected in maternal blood ‘ minutes 15 after ingestion, gastric lavage was performed, and camphor was not found 8 hours later. At delievery, 36 hours after ingestion, camphor was found in amniotic fluid, umbilical cord blood, and fetal blood, as well as in the liver, brain, and kidney of the infant. Cause of death. was failure to initiate respiration [Ref. 15). In a second case [Ref. 16) a healthy baby was delivered 20 hours after ingestion of camphorated oil. While high levels of camphor were measured in maternal blood 24 hours after ingestion and the amniotic fluid had a distinct odor of camphor, only very low levels were found in the infant’ blood. In both s cases (Ref. 9) the mothers mistakingly took camphorated oil, believing it to be ‘ castor oil, to induce labor. The treatment of camphorated,oil . poisoning is by no means simple. Most toxicology texts recommend symptomatic and supportive treatment. Treatment is complicated by the fact . that camphorated oil is highly soluble in’ lipid deposits. Lipid hemodialysis (Ref. 3 11) and resin hemoperfusion (Ref. 17) have been proven to be effective treatments, but the value of these procedures is constrained by their I limited availability. Reports of camphor poisonings have appeared in the literature for decades, with a large number of the cases involving the accidental ingestion of camphorated oil, often mistaken for such items as castor oil, cod liver oil, mineral oil, olive oil, and cough medicine @efs. 6, 9, 14, 18. 19, 20. 21. 22, and 23). The Panel concludes that camphorated oil is the worst offender of all camphor preparations that are accidentally ingested because it is mistaken for a variety of other OTC products. The Panel further concludes\ ’ : that camphorated oil is unsafe because ’ of the large number of accidental . ingestions by children and the potential toxicity in infants and young children including death (Refs. 1, 6. 7. 19. 20. and 22). Statistics compiled by the National Clearinghouse for Poison Control Centers record 706 ingestions of camphorated oil, 421 occurring in children less than 5 years of age, from 1974 to 1978 (Ref. 18). The risk of poisoning in infants and young children,

0

;e

.

%

(11 Sajcfy. In ils report on external nnalgesic drug products, which was published in the Federal Register of December 4.1979 (44 FR 69768). the Topical Analgesic Panel discussed the safety of camphor. That Panel stated * that case8 of systemic poisoning from topical application of camphor have not been reported. In his presentation to the Miscellaneous External Panel on January 281980. Mr. Varano pointed out that three cases have been reported in the medical literature [Ref. 1). In one case, camphorated oil was applied continually for about 80 hours to the . chest of a t-year-old child. The resulting diagnosis was camphor poisoning [Ref. 3). In another case, a 15-month-old boy became progressively ataxic and had some brief generalized major motor seizures after he crawled through spirits of camphor (a IO-percent solution of camphor in alcohol) spilled by a sibling. No further seizures occurred until 1 year later when the child was exposed to a. camphorated vaporizer preparation containing about 5 percent camphor. : Concurrent with this inhalant exposure, the child bad a brief major motor seizure. The authors concluded that the occurrence of seizures with only two camphor exposures, a year apart. dicates a specific sensitivity to this gent (Ref. 4). The third case was a near-fatal incident in a 6-week-old infant after an ointment containing camphor, menthol, and thymol had been rubbed on the chest (Ref. 5). The Topical Analgesic Panel noted in its report that the estimated minimal -. lethal dose of camphor in humans is 2 grams [g) [for a 150 lb. man) when . ingested orally and that one adult survived ingestion of 15 g camphor. The Panel calculates that the minimal lethal dose is thus 30 milligrams/kilograms . (mg/kg) body weight. However, ingesting 0.7 to 1.0 g camphorated oil ‘ . proved fatal to a child (Ref. 6). The Panel noted that accidental poisoning has occurred from ingestion of’ camphorated oil when it has been administered erroneously for castor oil and that cases continue to be reported. In information Mr. Varano submitted to the FDA pef. 1) which he obtained from Regine Aronow, M.D., Director. Children’ Hospital Poison Center, s Detroit, MI, Mr. Varano presented data on hospital admissions at Children’ s Hospital due to ingestion of camphorated oil. Between 1975 and the first 6 months of 1979. there were 28 ospital admissions involving ingestion f camphorated oil. Of these 26.16 were ue to accidental ingestion, 5 were due to ingestion of camphorated oil mistaken for,castor oil. 1 was due to an ingestion : . , r

of camphorated oil mistaken for cod liver oil, rind 4 were due to ingestion of camphorated oil mistaken for cough medicine. Mr. Varano also presented information which he received from the Provincial Drug and Poison Information Center of Vancouver, BC. concerning an ingestion of camph rated oil by a 2! year-old child whit I proved fatal (Ref. ’ 11. Jacobziner and Raybin [Ref. 7) reported a case in which an l&monthold girl ingested camphorated oil, had a convulsion soon thereafter, and was hospitalized several hours later. At the hospital, the patient had generalized convulsions, right facial twitchings, and twitchings of the right leg. The infant soon became comatose and died 4 hours after admission to the hospital. Death was attributed to respiratory failure. Whelan (Ref. 8J reported a case of a 3year-old girl who ingested an estimated 0.7 g of camphor (of a product containing about 5 percent camphor) and had a convulsion soon thereafter. An electroencephalogram 18 hours after the seizure showed some abnormalities. A repeat electroencephalogram 15 days, after discharge from the hospital was unchanged from the earlier one. An electroencephalogram 3 months later wasnormal. I The American Academy of Pediatrics Committee on Drugs @ef. 9) has presented a progressive . symptomatology of severe camphpr intoxication. The onset of symptoms of camphorated oil poisoning may occur. within 5 to 15 minutes after ingestion. although they may be delayed up to several hours if food is-present in the stomach to interfere with absorption. .Nausea and vomiting are usually the first symptoms to appear, followed by a feeling of warmth, headache, vertigo, mental confusion, restlessness, delirium and haIlucinations. Increased muscular excitability, tremors and jerky movements, and convulsions followed by central nervous system depression and coma may occur. In cases of severe poisoning, death occurs from respiratory failure or from status epilepticus. If death does not occur, mental retardation can be an aftereffect (Ref. 10). If the patient lives, recovery is usually complete within 48 hours [Ref. 11): . however, a 19-month-old infant died 5 days after the ingestion of 1 teaspoonful of camphorated oil [Ref. 5). ’ Camphor is readily absorbed through mucous membranes, subcutaneous tissue, and the gastrointestinal tract. In smaIl doses, camphor combines with glucuronic acid and is excreted via the kidneys [Ref 12). This mechanism accounts for its unusually high toxicity in fetuses and newborn infants because

.

as evidenced

by Ihe n~:merous reports ‘ lerature and by the National ‘ nghouse for Poison Control

in

(la

.

rs. is a msjor faclor in the Panel’ s assessment that camphorated oil is not safe for OTC use. Additionally, in reviewing toxicity in mice, rats, and rabbits. it appears that human beings may be 50 to IOO times more susceptible to camphor poisoning than the usual laboratory animals. The Panel strongly recommends that the FDA act swiftly to remove camphorated oil from the market. (2) EfJecfiveness. The Topical Analgesic Panel. in its report published in the Federal Register of Decembej 4. 1979 (44 FR 69768), discussed the mechanism bf action of camphor as a counterirritant and stated that it was unable to find any acceptable reasons for the continued employment of camphor alone as a topical

(5) Dupeyron, J. P.. F. QuHttruc.chi. II Custaing. and P. Fabisni. “Inloxicalion Aigue Du h’ ourrisvon Par ApplicalionCutHnee D’ Une Pommade Revulsive Locale et Antiseptique Pulmonaire.” Eoroyecln Joumof of Toxicology, 9:313-320, 1976. (6) Smith, A. G., and G. Margolis. “Camphor Poisoning. Anatomical and Pharmacologic Study; Report of a Falal Case; Experimental Lnvestigalion of Protective Action of Barbiturate:” Amer(con Journalof j’ ofhology. 3o.8s7-889. !95U. (7) Jacobziner. H., and H. W. Raybin. ( “Briefs of Accidental Chemical Poisonings in New York City.‘ New York Sfofe Joumolof : Medicine, 59:115-118. 1959. (8) Phelan. W. J.. III “Camphor Poisoning. Over-the-Counter Dangers,” Pediafrics, 57:42&-431. 1978.

(9) Committee on Drugs, American Academy of Pediatrics, “Camphor: Who Needs It?. Pediatrics, 62:404-406.1978. [IO) Arena, J. M., “Poisoning.” 3d Ed-. Charles G. Thomas. Springfield. IL p. 3% , 1974.-

x

4.1 I--R 71742) that this proposal is of a type that does not individually or cumulatively have a significant effect on the human environment Therefore, neither an environmental assessment nor an environmental impact statement is required. Therefore. under the Federal Food Drug, and Cosmetic Act (sets. ZM, 5OZ 505,7m, 52 Stat. 7040-1042 as amended, 1050-1053 as amended. 1055-i056 as amended by 70 Stat. 919 and 72 Stat. 948 (21 USC. 321, 352, 355, 371)) and the Administrative Procedure Act (sets. 4,5, and 70.60 Stat. 238 and 243 as amended (5 U.S.C. 553, 554. 702, 703, 704)) and under authority delegated to the Commissioner (21 CFR 5.11, it is proposed that Subchapter D of Chapter I of Title 21 of the.Code of Federal
Regulations be amended in Part 310 by

.

.

_

adding new Q 310.526, to read as follows:
p 310.526 Camphorated oil and camphor_ containing drug products. (a) Historically, camphorated oil (also

(II) Ginn, H. E.. e; al.. “Camphor
Intoxication Treated by Lipid Dialysis,” * Joumol of American Medical Assuciotion,
203:230-231.1988:

. counterirritant at the concentration (20 percent) present in camphorated oil. In a

statement on camphorated oil presented to the Miscellaneous External Panel on September 27.1978, the American Pharmaceutical Association (Ref. 2) state&
r&d&ring the length of its existence orated oil was officially recognized in t edition of the U.S.P.. published in _ and its widespread use. it is surprising * that a search of the literature failed to yield a single reference concerning the efficacy of _ camphorated oiL The Panel was not able to locate, nor is it aware of any significant body of data demonstrating, the effectiveness of camphorated oil when used as a counterirritant

(12) 0~01. A.. and R. Pratt Editors, ‘ The United States Dispensatory,” 27th Ed.. J. B. Lippincott Co., Philadelphia, p. 220,1973.
(13) Gosselin. R E.. et al., “Clinical Toxicology of Commercial Products,” 4th Ed..

The Williams
77.1976.

and Wilkins

Co.. Baltimo,re, p.

(14) Aronow. R. and R. W. Spegie). “Implications of Camphor Poisoning.” Drug lntelhjpnce ond Clinical Pharmacy, 10:631634.1978.

[IS) Riggs. J.. et al., “Camphorated
Gynecology, ZZZ55.1965. (16) Weiss. J-. and P. Catalano.

Oil

Lntoxica tion in Pregnancy.” Obstetrics and
“Camphorated Oil Intoxication Dm-ing Pregnancy.” Pediotics, 52:713,1973. (17) Kopelman, R.‘ al. “Camphor et. Intoxication Treated by Resin Hemoperfusion,” Journal of the American MedicalAssociation. 241:727-728.197’ 9. (18) Poison Contml Statistics, Food and Drug Administration. 1974-1978. 1’ Clark, T. L. “Fatal Case of Camphor 19) Poisoniug.” The British Medical Journal

_ .

known as camphor liniment), a solution of 20 percent camphor in cotlonseed oil, has been marketed as an over-thecounter (OTC) drug product for various uses, primarily as a counterirritant or. liniment. A large number of accidental ingestions of camphorted oil, often mistaken for castor oil, cod liver oil. mineral oil, olive oil, cough medicine, or other products, have been reported and toxicity has often resulted, primarily in,
infants and young children. Because of the potential hazard for poisoning to .

. ,

,

(3) Evaluoticx~. The Panel believes the hazards [i.e., the dangers of poisoning)
associated with the use of camphorated oil far outweigh any questionable. benefits to be derived from the medicinal use of this product. The Panel has serious concerns about the potential

for

poisonings

rf+sdingfrom

the

accidental ingestion of camphorated often mistaken for other proprietary

oil,

medications; camphorated safety.
References

therefore, the Panel places oil-in Category II for
Association

(I) OTC Volume 160383. (2) American Pharmaceutical

presentation on Camphorated Oil contained
in OTC Volume 160291. (3) Summers. G. D.. “Case of Camphor Poisoning.” Erifish Medical Journal, 2:1009. R R.. L L Ware. Jr.. and 1. E. Camphor.” Clincial
1977.

W. P.. and H. B. Curry. “Camphor Poisoning, Report of Case Du;ing Pregnancy.” Journal of the Florid0 Medical Association, 43: 999-lM10.1957. (21) Haft. H. H.. “Camphor Liniment Poisoning.“Joumol of the American Medical Association. 84:1571.1925. (22) Barker, F.. “A Case of Poisoning by Camphorated OiL” The British Medical Journ&, 11921.1910. (23) Bellman, M. H., “Camphor Poisoning in’ Children.” British Medical Journal, 2:177.- : 1973.

1:467. 1924. (20) Blackman,

Pedi&ics.

16:9X-902 ,.

_

All referencks are on display in the office of -the Hearing Clerk, Food and Drug Administration, Rm. 4-62. 5600 Fishers Lane, RockvilJe, MD 20857. The agency has determined that under 21 CFR25:24(d)(9) (proposed in the Federal Register of December 11.1979; /

occur, the benefit from using any drug products containing camphor and labeled as “camphorated oil’ or * “camphor liniment” or any similar name such as “camphor oil” or “camphorated liniment.” for any use. is insignificant when compared to the riskEased upon the adverse benefit-to-risk ratio, any drug product containing camphor which is labeled as “camphorated oil” or “camphor liniment.” or any similar name such as “camphor oil” or “camphor liniment,” ’ cannot be considered generally recognized as safe. Also. based upon lack of safety and effectiveness data and the adverse benefit-to-risk ratio, any drug product containing camphor in excess of 11 percent cannot be considered generally recognized as safe. (b) Any drug product containing camphor and labeled as “camphorated oil” or “camphor liniment” or. any similar name such as “camphor oil” or “camphorated liniment.” or any drug product containing camphor in excess of 11 percent offered for any use is misbranded under section 502 of the . Federal Food, Drug, and Cosmetic Act and is a new drug within the meaning of .

-

I . *

:

6~874

Fcdurnl .-.__

Register -

/ Vol.

45, No.

789 / Friday,

Seplcml)er

26, 7980

/ Proposed

Rules

.-

0

e -.

.

percenl ointment, SlCidm inhalalion-7 reopeniru the administrative record for ~cclion 201(p) of the Act for which an. percent solution, lozenge-O.02 lo 15 over-the<ounler (OTC) cold, cough, approved new drug application under milligrams (mg]); anlilussive (topical-5 allergy, bronchodilator, and section 505 of the act and Part 314 of this percent ointment. steam inhalation-7 antiasthmatic drug products to allow for chapler is required for marketing. percent solution, lozenge-0.02 lo 15 mg): (c) A completed and signed “Notice of consideration of recommendations on and nasal decongcslant (topical-5 Claimed lnvestigalional Exemption for a camphor-containing drug products that percent ointment. steam inhalation-7 heve been received from the Advisory New Drug” (Form FD-I 571), as set forth percent solution lozenge-0 02 to 15 mg). in 5 312.1 of this chapter, is iequired to Review Panel on OTC Miscellaneous Following the publication of this panel’ s cover clinical investigations designed to Exte&al Drug Products. recommendation on camphor, the obtain evidence that any preparation DATES: Comments by November 25, Advisory Review Panel on OTC containing camphor which purports td 1980; and reply commenls by December Miscellaneous External Drug Products be or is represented as camphorated oil 26.3 980. (Miscellaneous External Panel) also or camphor liniment or any preparation ADDRESS: Written comments to the reviewed camphor. The Miscellaneous containing camphor in excess of 11 Hearing Clerk (HFA-305), Food and External Panel, however. concluded that percent for any use is safe and effective Drug Administration, Rm. -2, 5600 OTC products containing greater than for the purpose intended. Fishers Lane, Rockville. MD 20857. 2.5 percent camphor have a low benefit(d] Any such drug product in FOR FURTHER INFORMATION CONTACT: to-risk ratio and recommended that interstate commerce after the effective William E..Gilbertson, Bureau of Drugs camphor be limited in OTC drug date of the final regulation that is not in (HFD-510), Food and Drug products for external use to less than 2.5 compliance with this section is subject Administration, 5600 Fishers Lane, percent. The Miscellaneous External to regulatory action. Rockville, MD 20857, 301&4434960. InterFsted persons are invited to Panel also recommended that the SUPPLEMENTARY INFORMATION: The submit their comments in writing quantity of camphor in a pa&age be Food and Drug Administration (FDA] (preferably in four copies and identifih limited to a total of 360 mg per package, published the report and proposed with the Hearing Clerk docket number preferably in a child-proof container. monograph of the Advisory Review found in brackets in the heading of this Because of the conflicting Panel on OTC Cold, Cough, Allergy, document) regarding this proposal on or recommendations on camphorBronchodilatdr, and Antiasthmatic Drug before November 25.1980. Comments. containing drug products, FDA has Products (CCABA Panel) on OTC cold, should be addressed to the Hearing concluded that resolution of this issue cough, allergy, bronchodilator, and would be in the public’ best interest. s Clerk, Food and Drug Adniinistration. antiasthmatic drug products for human. Therefore, the agency has-concluded Rm. 4-62, 5600 Fishers Lane, Rockville. use on September 9.1976 (41 FR 38312). that the Miscellaneous External Panel’ s MD 20857, and may be accompanied by Interested persons could have filed recommendations should be available to supporting memorandum or brief. written comments regarding this omments may be s&en in the above the agency in developing a tentative proposal by December 8,1976, and office between 9 a.m. and 4 p.m., final order on cold, cough, allergy. comments replying to comments by Monday through Friday. bronchodilator. and antiasthmatic dmg January 7.1977. After the closing of the In accordance with Executive Order products. By this notice, FDA announces’ comment period following publication of 12044, the economic effects of this that it is treating the data and _the panel report, new data and proposal have been carefully analyze/d. information on camphor received from information may be submitted for and it has been determined that the the Miscellaneous External Panel as a inclusion into the administrative record proposed rulemaking does not involve petition to reopen the administrative only through a petition to reopen the major economic consequence3 as record on cold, cough, allergy, administrative record. defined by that order. A copy of the bronchodilator. and antiasthma$c drug In a notice published in the Federal regulatory analysis assessment products. FDA is granting the petition by Register of March 21.1980 (45 FR 18400). suppo&g this determination is on file allowing the data and information the agency advised that it had reopened with the Hearing Clerk, Food and Drug contained therein to be included in the the’ administrative record for OTC cold, Administration administrative record for OTC cold, cough, allergy, bronchodilator, and cough, allergy. bronchodilator. and Dated: Sepiember 15.‘ 1980. ’ . antiasthmatic drug products to allow for antiasthmatic drug products. This notice Jere E Goyan. .consideration of data and information serves to inform interested persons of Commissioner of Food and Drugs. that had been filed with the Hearing these recommendations, which appear (Fn Dot Bo-z99M F&d %25-80.8.5 am] Clerk’ Office after the date the s below. This reopening of the BlLlJNC CODE 41 IO-034 administrative record officially closed. administrative record relates only to the The agency concluded that any new -ingredient camphor in OTC drug data and information filed priofto products. Comments relating to portions 21 CFRPart341 ’ March ~1.1980 should be available to . of the Cold, Cough, Allergy. . [Docket No. 76-N-521 the agency in developing a tentative Bronchodilator, and Antiasthmatic final order. Proposed Monograph (4’ FR 38312) other 1 Cold, Cough Allergy, Bronchodilator, The CCABA Panel concluded that than on camphor will not be accepted at and Antiasthmatic Drug Products for camphor is safe but the available data this time. ’ Over-the-Counter Human Use; were insufficient to determine whether it Statement of the Advisory Review Panel Reopening of the Administrative is effective when labeled for use as an on OTC Miscellaneous External Drug Record OTC expeclorant, antitussive. and nasal Products Concerning OTC Drug . decongestant. The Panel placed Food and Drug Administration. Products Con!aining Camphor camphor in Category III [available data CTION: Reopening of administrative are insufficievt to classify the ingredient The Advisory Review Panel on OTC as Category I or Calegory II) for Miscellaneous External Drug Products SUMMARY: This notice advises that the different uses at different has reviewed the product camphqrated Food and Dpg Administration (FDA) is &oncentrations: expectorant (topical-5 oil as well as numerous other camphor-

\

, ec,,~u~NTP.R’ ES
.?-dren and Teicvision-R. .\.+ments of Pediatrics-R. J. Feinbloom J. Haggcrty

,;~TICLES ,,,cclla Gangrenosa Due to Group A /?-Hemolytic Sfrcpfncoccus-E. P. Smith, . A. Carson, Jr., J. A. Boyleston, S. L. Katz. and C. f4. Wllfert L.tiobic Infections in Children-L. M D!lnkic, T. J. Brotherton, and R. D. Feigin ,- V,rtnerabilify of the f4cdicnl Student-E R ‘ Sterner and B. f*1. Korsch on Television Cause Apathy?-R. S. Drabrnan and M. R >* Watchtng Violence Tbcmzs Anomalies Associated With Congenitai Condu&ve Hearing Loss-B. F. Jaffe Durin g Quiet Sleep in Two Infants-D :cntral Hypovcntiiation C. Shannon, D. W. %larsland, J. B. Gould, B. Callahan. I. D. Todres, and J. Dennis R-&Me and Clinical Features of Patent Ductus Arteriosus in Low-Birtilweight Infants-B. Slassl. C. Blanco. L. A. Cabal, and A G. Cordn ‘ Role of Artificial \r Ventilation, Oxygen. and CPAP in the Pafhqenrsis of LlJIlg Damage in Neonates-J. S;ocks and S. Godfrey nu;~rn Responses During Catch-up Growth of infants Who \“Jere Small for Gestational Age-E. Colle. D. Schlff. G. Andre:Y. C. B. Bauer, and P. FI:rhardtnge : 4% for Children About Death-C F?. Ar?dine -mod Cysts in Children--L. F. Pcllard, R. D Harley, and J. Calhoun @unce With Short-Term Antimicrobial Therapy-J. Lima, L. Nazarian, ,’ Jnd C. Lahti ‘ *Jpe of Hemophilus influenzae Type b Meningitis After Combined Therapy-W. E. Feldman, W. E. Laupus, and P. Ledaal E. Charney. Antiobiotic

q3ATRICS FOR THE CLINICIAN ‘ prdlatrician and f4aipractice-R. k H. Erown 4 lrrtematic Review of the Literature on Evaluative Studies of Tonsillectomy anti Adenoidectomy--W Sharkh. t. Vayda. and W. Feldman wry Travel for Children With Chronic Pulmonary Disease-Cardiovascular CommIttee of the Cyshc Fibrosis Foundabon . “fRCAN ACADEMY OF PEDiATRlCS ‘ *tl of Cigarette-Smoking on the Fetus and Child-Committee on Environmental Hazards ‘ *ud-Task F orce on Pediatric Research, Informed Consent, and Medical Ethics ‘ Q?nt Status of Ampicillin-Resistant Hemophilus influenrae Type b-CommIttee on . ‘ hfechous Diseases . I-

,
‘ ERCE AND RFASON-BRIEFLY qS’ RECORDED w Crmsequences of imitative Behavior in Children--J. Daven. J. F. O’ Connor, and 4 Brl&gs “O*til”m-A D angerous Laxative-G. Rosenstein. H. Rosenstein, M. Freernan, and ‘ 1” f reston “-*nt of Acut e S ore Throats-L. Gordis, L. Desi. and H. R. Schmerler qcr*occal Cervical Adenitrs in Young Infants-J. P. Hlcber and A. T. Davrs ““4 Blood Lead in a 6-FAonth-Old Breast-Fed Infant-K. C. PerkIns and F. A. “ ** ‘ poisoning-w. J. Phelan. III ‘ r yy9*e~ous Lymph Node Syndrome in the d’ dsmlth, P. Grlbetz, and L. Strauss

Continental . -. PEDIAU :

United

States-R.

W.

:. 5713)
Do. 31)i-438 119761

Two’ C~SCF with documented w-run camphor levels have prompted this report and discussion of camphor’ role in the self-medication over-thes counter amlamentarium.
CASE REYORTS Case P

425

PEDlATRlCS

Vo!

57 No. 3 March

1976

A
c-zz/L.-;;; ___.

~AI~T~AL ._.... -.

LI~.~-INC .---^_.--

OF

AvAllnlc1.L: -..._

Ovr ~.-

n-11:1 ..-. L....~_

Co:.> -.----

il.]! -

!‘ 41LAT,‘ Nl:i’ mI .:-?iJ .z-IL...-.

<:~,“;r.rlsrsc,

Chvt’ llol~ ..._-I_.__

_. _.^---.-

---.--.--.--.---z-----

____-_ -..-..-~i,q’ l,oratt!d oil _-.--------(inll,ho-l’ henique _-------ci,nl>hor spirits ___-----%lt,t.e Hi-Therm An:iiFesic Ualln -_----fkncay Children’ Rut1 s --&,lt,ce Quick-pub (Adult) &~alve 5; \‘ lckc Vapomb -x pamlgesic Heet .kitice Quick Rub (Children’ s) _-__Sloann’ Liniment s ia-Camph Arthritic -Lni-Ha!m Aerosol Foam .4nalbalm Sloan’ Balm s Rhulicream Slusterole Pmetro Quick Acting Rub -vu-Tro-h”oI Solttce Hi-Therm Lotion

Frdtrc,f

_.-

-__-----

hfnnflj-*rcturer

-. --_Various

__-.. .-..--~_.~-. 20.00 10.80 -____ lo.@9 7.00 -6.00 ------..5.10 ___ 5.00 .4.61 4.Go ~-__--4.00 ___I__ 3.75 3.40 ---.

CfirrcJllWr

__---__

Clcnbrook ----__----Various -___-___~. Chattcrm Pfizer Chattem Carson Vi& Poythrrss BGehall Cim.ttcm --Standard Dorsey Chattem Amar-Stone ---Central Standard Lederle Plough Plough Vick

Dosage E‘ onn - .--.---Extcmal analg~~sic mb --External analgesic rub External ana!gesic rub

_._--.-~._ -_~External analgesic rub ----External analgesic rub External analgesic rub .. External analgesic rub -_. External analgesic rub External analgesic rub External analgesic rub ._-EXemal --External analgesic rub _-EMemal analgesic rub -___ External analgesic rub Ejrtemal analgesic rub External analgesic rub I External analgesic rub External analgesic rub External analgesic rub _-External analgesic rub Nose drops 3 analgesic rub -

--

3.00 3.00 2.00 .-I___. 1.50 0.50 0.30 ? ? ?

hy the liver, with excretion of the inactivated (Qrnpound in the urine. * This dctoxiGcation ocPUS rapidly and accumulation bv chronic inlraQMl application seems unlikelv lkcnuse cerebral Ykl fluid and serum revealed no detectable calnphor 21 hours after ingestion in case 1. Riggs +’(11,‘ patient: had no detectable amount eigllt s

stations of camphor intoxica,ntral stimulation associated ;~r:d gastric irritation. Nausea ,lcntal changes such as excite7, and dcliritlm are common. hiusc~l;~r excit:ilGli Y and tremors may herald the onxet of gc~~.:rali~: .; convul~ionr. often followed by clcpreion ;miJ apnea.‘ Urinary ” retention. anliria, and ;II~HFL:II -:i~ria have bcon dcscribctl as well as traIisicr;l II Ild licpatic ch;t~:gcs.‘*~ Rul)in cl cfI.” PC] .>rtcd convulsions in five of 14

hours after matern well except for an i and SGPT.” The major man& tion seem to tre c with mouth, throat and vomiting w~7jflb ! ment, hallucin:itici~

il ingestion. The infant did ,.:rly mild elevation of SCOT

Statistics COil?J>ijed by the National CkaJillghowz for Poison Control Cc~lters record 185 ingestions of camphor, 133 occru-l-iII;: in children less than 5 years of age in I%,‘ and 1959.’ Forty; sk percent of ailai\rL<:d patients had sylnpioms and Xl?; had corl;isions. Fifteen years fater, in 1’ 373, there were reports of 5% ingestions, 415 occurring in clliltlren less than 5 years of age.3 in Camphorated oil and spirits \vcrc: implicated poiwnings, with t3ie 4Wb of the childhood remainder invol\TinF; otllcr over-the-counter preparations. In all cases, symptoms Lvere f?resent in lS?O and con~~llsiorls in 4%. Convuisions associated With Vi&s Vaporub, quantitat.ecl serum camphor levels, and electrotncc;~halogr::phic abnormalities have not been reported previous-

u:

j Food and Dn~g Administr,. .i!lg over-the-counter prep. ~11ly evaluate the bcn~f~t. m;:ug~ such as camphor rrxf i apidity an increasing p~rt)lK ‘ rmaceritical houses prcdtrc-. ,.‘ lould voluntarily rcatrr dnd market only prcp3ra a -: wi&& clear warning Idhrlr 1~s of potentially dangcrour cnmpllor are present. .T.IAM J. PHELAN III, 3i.D. ,:rrtment of Pediatrics and ,)mmunicable Diseases, Tersity of hiichigan hlcd~rz! ‘ enter

ediatrit- w’ ADDIIESS FOR REP>-; .TS: Department of I’ Communicable Div.:s, Arbor, Michigan 4811): , !slott Children’ s IIos@tat. .4-

.ly.
Treatment should include immediate induction althou@ both caSe 1 and case 2 of vomiting, sugest that early ernesis did not completely empty the stomach and absorption continued. (;;&ic Iavage may be helpful in removing remainins material and activated charcoal taken orally or placed into the stomach at the termination of lavage is also recommended to absorb oils and alcohol slrould be residue.‘ Digestible ” avoided because they enhance absorption of camplLor.G Int~nvenousI~ administered barbiturates are suggested for seiz~ux control, and lixnited animal data sqgest they have a protective effect on the central nerVorl; S):!jtem.* iipproprixte respiratory support is intlicatcd for deprcsand minision and apnea, and close olwrvation mized sensory inpklt are important for s?.mpton;s of escesG\-rc centr31 stimul:ltio:l. f3stracorl~c~renl i, qi Q lii)iti d’ I 1)8. 5 112s 1uxn s~lccessf~ll in an adult wl,o ingested 12 gm.13

REFERENCEI. Slnith A, Xfar~o!i\ 30.857, 1’ 351. 2. Verhulst HL, Pay Child 10153~ 3. National Clrarir81 \Vashingtorr ! 4. G&man L.S. Gil Therapeutics. pp w-w. 5. Griflcnhagcn GI?. Prescription I’ hannxeuti~ 6. Gleason hIN. (:! Clillical ?‘ ou. l~altinlore, \: 55. 7. Ri;;g\ J, IIamiltor~ oil. intoxtcxt, 25:255. 1x5.

430

CAMPHOR POISONING

.-’
EiJitorkl.* . _ . _ . . . . . . . . . 4.1

.. .. _ .’ , > ’ ,.,’ -5

.

*

,-

.

.

,

1”

. -I,

(

/,

1’ .

-,.

/.

,,

.

. j. : : 1 (, ,’

J:,

_-

.

--rc---:

-~--

__--_-._--I----

--

“..

All three rwovercd. TIIE.~T.\IE~~.----C3IIII!hor J~o~o;~'~:," trr&c Case 3: U’ hiie the gmndmother 11.3~ the mcnt consists of rcmo\~al by la=,( .o of the in kit&n, her fiftwn-month-old grandtlnughgastric cwtenfs. Ilon.c\-er, 13~~1‘ should 2 ter climbed ;m a ch:Lir, I oak 3 hot tie of c:~m- not be done during LI con###BOT_TEXT###amp;i: ‘ att.wk 3 p,hornted oil from a dre%wr in thr li\.ijlg room, opened it, and drank about a trqwo~lful. The child immedintely hnd abdominal p:Gns, stupor, convulsions, etc. Thechild recovered conlp!etely. Co-se4: A seven-yew-old girl cornplnined of a cold, and her mother told her to g:o into the l&hen for a spoonful of cod-liver oil. The. child dislilwd cod-liver oil so she event inste:ld to the batflroom to t&e r:t,stor oil. Srw mktaknly obtnirwd ct bottle of c:h~r~p!~orated oil and ingest4 OIX tat,lc~~~c)or!ful. The child immedi:itely complnincd of a burning in the mouth 3ld thro:tt :ind ~53-5 ru.J~f-d

.I ,‘ a

.-- ..___ __.-_.. ,--Ij_c/” -.., ,-..

s

I

.

. .

I_

i.’

/----..

c *

VISUAL

‘ ,2r13 I‘? 5 8 .

JANUARY

l-MA~CH2&

*.

*. 3 a

::. ..

c_ t-’

-.. - -_---....__. - -.-..--..--..--- - ..._ ^__... I - _-._.__.-_- -.__.. ’ I

A

Amberllte

Column

A

A

0
Coil l3ialyzer

J
:rs After
Fig l.-Schematic ‘ 71~~1s ohlalned diagram at pomts of dialysis system. A, 8, and C. E3lood samples for Ftg Z.-Plot of placme c C vs tme. Mayor citmc. represent VQ~OLIS. srji ’ hemodlalys,s. Ingestion A. 6. ati Tnangl*l pos111pd -..,ohor levels obtamed at points ‘ .vPnts noted on vertical axis. li, posthemoperfusron; circles.

Once used as 2 reflex respiratoit is now used cxclusively for its lwal actions.’ In a recent report of two cases of accidental ingestion in children, Phelan’ cornpiled a list of 21 over-the-counter preparations containing as much as 206 camphor. hlost reported cases of intoxication are accidental, either b\ inadvertent oral ingestion of a topical preparation or by confusion of camphor for rod-liver oil, a coli, prcparation, or castor oil.“““’ Deaths have been recorded from ingestion of as iitrlc as one teaspoonful of a proprietary preparation.’ Description of the clinical aspects bf intoxication have been remarkably
rq‘ stimulant,

skin.

consistent during the past three decades. Craig” describras four cardinal symptoms. increased muscu!ar excitabi:it:;, abrupt onset of cor,vulsions, von:iCng, 2nd mental changes such as confusion and transient behavioral chaI;gcs. Since camphor is absorbed in five to W minures and its ahsorprion is enha,lced by coingestion of alcohol or fatty material, rapid intervention with induced emesis or gastric lavage is indicated in 2n
attempt to prcven! absorption.“ ’ Enr-

r;ies suggest that neuronal damapc i occur. tie information is available COP ruing toxic levels or distribution CL iphor following absorption. 1:~ *II lipid solubility suggests accurnu :on in adipose and other tissurc i ronsequent delayed excretion.

ly reoorts of death bl; rtaspirators fai!ure!‘” may have been the resu!t of aspiration cr status epilepticus. The mechanism of neurotoxic effects from camphor is unknown. but several

Nonproprietary and Trademarks qmmazine-Chlor-PZ, xchel. Thorazine

Name of Drug Cmmedm~. f+

728

JAMA.

Fob

16,

1979-Vol

P41,

No.

7

Intoxication
Robert Kopclman,

Pi-eateci b; 1 Resin Hemoperfusioia
.W.?: Sanford h?l’ lcr, 3, Raymond Kelly. PhD; lrvmg SunshIne, Pt:f.

During the night, tk.? ;laricnt’ s t1100d precsure mas maintainc~d irh 2 liters of normal saline IV. At S A\: he uncit rwent bronc!ro~,ropg for rc;,x!.nr)Gon of a collapsed right upper lob<* secondary to tht: initial aspiration. Whiles nia!ntalning normal
tose

vital
wi!h

signs
recurrenl

wth

sdequrltc

ac:sisted

ventilation,

the patirn?

remained
xtivitv.

rorna})I.-

sri::~:rra

;sed and shown
dality.

And less cumbers3rne

to be a new, eifpctive, therapeutic mo-

Report of a Case
A 37-year-old man came to the emergenQ department at l:S@ AL! because of zMominal distress. A friend who accompanied him inc!icntrd that the patient had ::.gested part of the contents of a IZO-ml to!!le that contained camp:loratc:d oil W& camphor) which he apr,a:ent!y had Gtaken for castor oil. Approximately 30 al remained in the bottle, sugges:ing that ahut 18 g of camphor may have beer, ‘ gested. The camphor \vas inpcsted at “ 11.M PM. The patient vomited at 12:lO AM ‘ a second time before arrival. He was cd ‘ :trt when he walked into the emergency &Fartmcnt, but minutes later, grand ma1 uiwes abruptly developed and he aspi‘ *ted before he could undergo intubation. hIlowing inttzbation, gastric lacayre was breath, and urine Prformed. His vomitus,

cause he had inzestcd a ~~,iltentiAl~ ielba! dose of camphor and fallen! to show clinic:*! improvement, au artemp: to remove t?lf absorbed camphor v.ras iixiicated. The only procedure reported at the time to be successiul in, rc:na\,.zi of abiorh4
Camphoi
Lvas lipid hernod!:,;! sic zcsinst z5

soybean oil bath.! Ginn et al’ re;)orttd clinica! improvement in a patient and recove:g rri !:irge amo3nrs of camphor in soybean oil rmpioyed on :ne dialysate side of the membrane brcauie of the high Ii,Jid solubility of camphor. Amberiite htmoperfusion resin, a stable copoiymer of polystyrene and divinyl benzene, recently has been used for the treatment of drug intoxication by hemoperfusion.’ The ambcrlize resin is n nonionic absorbent with numerous aromatic func:ional groups that render it hydrophobic. Thus, it h::s high a:?inity for selected dregs and other r:onpolar organic molecules 6’ .4lthough these characteristics recommended its use for the rezo\.;ll of camphor, amberli:e hcmnpcriusioo renin had not been demonstrated to be effective in humans or in aci:~:;;~s for removal of camphor. Therefor-e. It was decided lo perfuse the patient’ s blood through the amberliie cartridge hcmoncrft:sion s:stern z:ld to follu~v this by lIri:j hrmodi;~lysiu. which not only would ns.;l~re that a mcthod tirmonstratod to bc eiiective was used but also would permit evaluation of the amberlite hemopcrfusior, ~~rocedurc. The 3yste.m em~!loyrd is shown schematically in Fig 1. lilooi samples were obtained for nnalysls nt the points indiCn r,

rated (A. U, and C). Vascular access for l,emodiziysis biood was obtainc>d from the left felrioral vein via a catheter rzserted tl:. the Se!dink:er technique, with return to T;C sntecuhitnl vein. Blood flows lucre ~::nlntainrd at 200 ml/min. Csmbinerl hemoylrrfusion and lipid hemodialysls Here performed for 45 minutes, lvhrn clottin,occurred in the hemoperfusion cartridge ) ,~ccause of an underestimation of the Iirparin sodium requirement for the combined system IIialysis \vas resumed for an zdditional three hours and 45 minutes using liquid h?modialysis alonca This re(riF.-‘ was coniplicated en by the cracking of the plastic czc:jn:: for an EX-2 coil dia!!-zsr on t~.o occasions. Two hours into rhe ?ie:nodiaiysis, a Travenol U-II I j-59 m co11 dialyzer \vas substituted for the EX-‘ 2.5 znit. and no further difficulties were e!;countered. After 2!h hours of therapy, !hr patient \~a? l:gzn to awaken, and the proceriure -<rminated e!ectively after an kditional . co hours. At that time, the initla! strone ,,:ior of camphor on the breath u as almost ,rone. His subsequent hospital cocrse u’ ;ts .,qeventful. He was fully alert the next 7 morning and was discharged the following :,v. Plasma samples were analyzed for camshor by gas chromatography (FiE 2). The liasma concentration just before the start -.f the treatment was 1.7 fig/ml; a secona ample taken 15 minutes into treatment . ..ic!osed a venous plasma level of 1.8 :/ml. Simultanenus samples taken be>veen the hemoperfusion cartridge and ‘ hemodiaiysis le system and after rhe pid hemodialysis system contained no xtectab!e camphor (less than 0.1 pg/ml). jasma samples obtained before clotting .’the hemoperfusion system thus showed .~~ontially complete extraction of the ~.:rnphor by resin. Subsequent samples ,rtnined across the lipid hemodialysis stem alone revealed about GO.2 cxtrac.,n. Thus. the amberlitc system appears s,,erior to lipid dialysis in its ability to &act camphor from blood.

Comment
Camphor is an irritant

ruhcfxicnt

when

thnt applied

acts as to the
727

‘ %

Fob

16. ls7s-Vol

241.

No. 7

or Inlow!cotion-Kopolmnn

ot nl

t .! l 7 ,

A

A

Ii

e
Coil nialyzer

4 10
Ftg I.-SchematIc oblamed diagram at pomts of dialysis system. A. E3. and C. Blood samples for

1;’ t :rs After ingestion
-slphor levels obtamed at points ‘ .\tt=nts noted on vertical axis. .3, posthemoperfuslon; circles, A. 8, rti Tnanplrl postilpJ

.‘ m

'4ly.515

Fig ‘ ---Plot of playma c 2 C vs time Mafor cilntc represent venous. sot..’ henrodlalgsla.

skin. Onto used as 2 reflex respirator?; stimulant, it is now used exclusively for its local actions.’ In a recent report of two cases of accidental ingestion in childrrn, Pheian’ compiled a list of 21 over-the-counter prcparatioris containing as much as 20% camphor. Most reported cases of intoxication are accidental, either by inadvertent oral ingestion of a topical preparation cr by confusiofi of camphor for cod-liver oil, a coli, prcparation, or castor oil.iJ’ S Deaths have J9’ been recorded from ingestion of as littIc> as one teaspoonful of a proprietary preparation.’ Description of the clinical aspects bf intoxication have been remarkabl)

consistent during the past three decades. Cr;lig” describes four cardinal symptoms: increased muscl;!::r excitabi:it.- .’9 shrupt or‘ set oi cor.vclSims, vomiting, 211ti mental changm

such as confusion and transient behavioral ChtiIipS. Since camphor is absorbed in five to W minutes and iLs absorption is cnha,lced by coingestion of alcohol or fatty material, rapid intervention with induced emesis or gastric !avage is indicated in an attempt to prevent absorption.‘” Ear1~ reports of death by respiratory failure”” mq have been the resu!t of aspiration cr status epilepticus. ‘ The mechanism of neurotoxic effects from camphor is unknown. but several Reforencm

dies suggest that neuronal damarr s (Iccur. ele information is available cop ning toxic levels or distribution o! ipl;Or following absorption. 1:) ,11lipid solubility suggests accumu Ion in adipose and other tissurc 1 consequent delayed excretion.

Nonproprietary and Trademarks

Name of Drug

728

JAMA.

Fob

16, 1979-Vol

341,

No.

7

October

14,

1976

Robert Pinto, Esq. OTC Drug Evaluations Director, Food and Drug Administration 9000 Rockvflle Pike Rockville , Maryland 2 0852 Dear Bob: I enclose five copies of my recent letter to the Co- .,,m!ssioner concerning camphor along with a cited reprint and the 1974 data of the National Clearinghouse for Poison Control Centers - the 475 camphor ingestions lsading to 77 hospitalizations represent an estimated 10% of the national cases. Since camphor is an ingredient of unprorren benefit in the cold exterra! analgesics, miscelland cough remedies, hemorrhoidal remedies, aneous external medicines and possibly/ other catt?corii’ s as well, I think some unanimity of opinion is In order. I think I can speak for pediatricians in genera! and th.? ,Imerisan .Association of Poison Control Centers in particular, in saying that if anything it is the redact!on si risk from toxic is to come from the c)TC panels, anachronisms such as camphor, Vlith t~est regctr-ds ,

C ad
Carol R. Angle, M,D. Professor of Pediatrics CRA: mls enclc : ures

RECEIVE3
-I _,

0

TrlE

UNIVERSITY s

OF

NERRASKA THE’

LlkcOLI** UNlVCRSli V Or NCijRASKA MEDICAL CENTER

October

5, 1376

Hearing Clerk Food & Drug Admin is tra:ion Room 4-6s 5600 Fishers Lane 20852 Rockville, Maryland RE: Docket No 76-N 0052 21 CFR Part 341 Monograph for OTC Cold, Cough, Allergy, Bronchodilator and Antiasthmatic Drugs.

To the Commissioner: There is sufficient pediatric concern yvvith camphx pziso:As noted on page 38.106 IF the safety of this ingredicn... little as 0.75 gm of camphor has been fata! to a chi!d”, dence that warning labels are any deterrent to childhood recommend that the camphor content of OTC cold and cc” fact, of all OTC medicines, be reduced to !ess than :?.I; than 2 . 5% VJ : IT’. This wgu!d reduce :ht7 risk of serious C i( while allowing an adequate cor,ccntration of camphor. Respectfully submitted, : : (1 ,2! ti? rez?r,siier <spt 9, ?976:, “as :e th,ere is no +z’ J!: s.oning , i WOUl3 .L.AA.< ~-cIT~~;~s and, in :‘ 30 grn or to less ir,t,i! Fzis3,nin;

Carol R. Angle, M. 1~. Professor of Pediatrics Past President, American Association of Poison Control Centers References: 1. Aronow, R. 1. : Camphor 1260 (Mar 221 1976. poisoninia. : :;m JV!ed Assoc 23:

2.

~~.*~zr the counter PheIsn, M’ .:.: Camphor potsoninc;: Pediatrics 57. (March\ L’ !F5. --- 428-431

dangers.

CRA:mls .
THE UNIVERSITY OF NEBRASKA LiNC0I.N TtiE UNILEYqr,l:Y DF NUBf?ASI(A AT OhlA+iA

i i

w

OI

-

Camphor

Poisoning

F ?r! S n;
( ut k :rlf a5t 1 t re3 sh

Extensively used in ancient Chinese medicine. constdercd the “balsam of disease” in the 16th century. and htghlv rcprded as a “circulatory and heart sttmulant” in the llte 19th and early 20th century,” camphor is listed in the US Phn~xopoe~~~ (ed 13 { rcvrsed]. I 974) as a topical rubefkcnt to provide local analpcstj. and antiprurittc effects. i’ cw publrshed studies, however, define camphor‘ precise s +um.~cologtc acttvrty or justify its inclusion in the Pb‘ ~t??l,iropejfl. Because of its supposed mrld expectorant and rarmln3tive efiects, camphor remains a component of pareporrc. Cknphorated parachlorophenol is used in derrttstr), as an anti-rnftc-ttve for the treatment of root canals. Camphor 1s ko used in flexible collodron Apart from tradrtion, It 15 hard to justtfy the mclusion of camphor m these products. Spirtts of camphor and camphorated 011 (cottonseed o:I contatnmg 20:) camphor) are readrly av.tilable n~tthour J~:etcrlptmn or Itmttation for either purilraser or use. For more than 100 years, poisonings from these substances h.:\e been reported rn the literature a Recent statIctIc s iron1 Naticinal Clc-dringhouse of Poison Control Centers shot\ .mnual Increase of camphor poisonings that rrdched apI~rnximately YOO cases in 1373 From the literature and from elycrrence (94 cases in 1374) at the Children’ 13OSpit3f s of hltchtgan, it IS apparent that the majority of potsonings, In both children and adults. are due to confuston that result\ In the substitution of camphorated oil for other patented medications-most notably castor oil, cod liver oil, c.lstorra, and cough and colrc preparations. As little as o 7s cm of camphor (one teaspoonful of campiloratcd oil) tan result in life-threatening rllness. Whether it IS the toddler ~.ho takes a swallow from an accessible bottle or the .Idult who mtst.lkenly takes several ounces, serious poi\ilnlt:q usually occurs. Jo additton, canrphor crosses the yl~rcnt;i ami has been tmp!rcated in ncon.ltal death.3

i-11 1tk TX rth i .jU’ tr)e ttc ‘ 9 t tc ela

‘ he. $31 :re c e flu ‘ . )‘ ry ton \s ‘ ian sta ice, A less ntl ---I I;la is. Wll of our ds i hat be ds n tJ Tw -b rf Ire cieri Chil es yer et 3 illl~l O? rtiti,ll n, unor lea1 i et1 ur ned to .(‘ ‘ \I or3tlon
I ilsewhet :c -.r am? K

-14 ‘ osis /III

am 1 rer.4 1
set! a,

‘ year!. at: Y :dlndry Clexlr,

1 hrnick

F

1260

.JAMA. March

29. 1976-Vol

235, No 12

7-C: FRQ!d : SUE~;:c-i :

John T. McElroy Harry E. Morton

Camphor

At the- last meeting of our Panel I was told to rework the mats.rial on are camphor and have it sent to designated Panel members as a suh:-lission._lEficlcsed 11 copies which I hope you will see fit to assign a submission number@@mail a u$j(‘ CF 3 copy to each of the following Panel members: g&J zz "0 Wm. E. Lotterhos Rose Dagirmanjian J. Robert Mewson Yelva Lynfield Harry E. Morton Marianne N. O'Donoghue Chester L. Rossi Albert A. Belmonte Jon J. Tanja John T. McElroy Thomas J. McGinnis %Ex C‘ -)c, z42 6% * 5 0-j

'

..

I tried to use only submission numbers and concentration of camphor, as you suggested, so liaison members of the Panel could see it b:Jt I found that in a For t3at reason I guess the couple of cases I needed to mention names of products. - material ought to be sent to only those members of the Panel ;Iho are permitted to receive classified material. Either I hope this finishes camphor as it has been worked over frequently. camphor is of equivocal value or some of the evaluators didn't do a good job, or maybe started it with the first draft in late 1975 or early some of both. I see Lotterhos 1976; Dagirmanjian followed with a second draft in May 1976; I took a shot at it as part of a review on ketones in December 1976 and evaluated czxphor products in Februal y 1978. Tanja revisited camphor in September 1978 and I.:;?Ifield took a swing at My memorandum of December lrj78 on summarizing and camphorated oil in October 1978. evaluating the various actions taken by our Panel and Topical Analgesic Panel got emascularcd. -Now this is, I believe, the seventh attempt at %:etting some logical evaluation of the camphor products. I hope it will be acceptable. to seeing rw
Enc.

Iq all goes well you on the 18th.

I hope to return I

from

meetings

on May 15 and look

forward

Jlarry H. Morton WI-%I',-79 Apprais:
11. Of CLlRi~>?JC~I;Ji: <Ill TJl::i-t ’ Fc 1Jt i 1-l a?mf‘ f,

i'? r~J~ar:‘ on:;. ;~f:j various However, purposes since

Camphor as an ingredient by physicians Tidscombe certain quent in and by individuals 1897 first in

has been used for for self its

ag;zs for

med-icatj-on. toxieIty oil

cautioned the sale of

about

and recommended t!ierc have been freof a century recommen-

precautions warnings its duriug toxicity

camphorated

the past and lack

more than of

three-quartt-:rs

concerning dations in the

effectiveness i.ts availability

ant: numerous

have been made on restricting treatment of others, by groups especially

to individuals Th<,se recommendations in protecting and the

children.

have been endorsed the health American of

of individuals namely

interestrd

individuals,

the Academy of Pediatrics

Pharmaceutical

Association. manufacturers precautions becomes and dispensing to protect pharmacists from have this

The pharmaceutical not taken the necessary Ingredient group out for to take that

the p~.!blic

poisonous trative pointed account is

so it

the‘ res20nsibilit:I, action. Aronow coupled that with

of some adminisand Spigiel human error action from that the in 1976

the necessary

"widespread poisonings these

availability and suggest archaic

camphor

admi'rzistrative rjroducts is hoped

essential place."

to remove In the

and unnecessary stated "It

market

same year

Yhelan

the

Food and Drug Administration preparations of ing drugs public While camphor will realistically

panels

investigating

over-the-counter ratio

evaluate

the benefit--versus-risk greater rapzdity

such as camphor health it is

and assume with

an jncreas-

advocacy." frequently is rare, pointed in all out fairness that it current3y should death from out that

poisoning

be pointed

2

such as hemodialysis, tion and laboratory procedures. year

peritoneal tests It which is

dialys-is, in

stomach

l,?vage,

heavy

seda-

some cnscs in submission of

requir‘ c

sophisticated during poisoning and that the

hospital calendar reported of these

stated

16Ct222 that of camphor

1974 there

was a total

542 cases Poison

to the U.S. 77 cases,

National or 14.2 cases

Clearinghouse percent, required

C:)ntrol

Centers

were hospitalizezl. a visit average cost to a physician of abo:lt cost expens.: a drug of

Assuming

the non-hospitalized emergency the this

or a hospital each and each,

room at a conservative cases an annual dollars to represent

$50.00

77 hospitalized represents

an average medical from

$3,000.00 of over

unnecessary
treat

a quarter beneficial

of 5 million effect.

poisoning

YE dubious

542 non-hospitalized 77 hospitalized

cases cases

@ $50.00

= = -

$ 27,100.OO 231,100.00 $258,000.00 Association that camphor i

@ '$3,000.00 Total

*

In

submission Control

160222 a past Centers

president - of

the iir:. srican -..

of Poison

and a Professor to less than

of Pediatr'rs .-- recommended 2.5 perccrt-: . (W/V> to reduce .-

311 OTC medicines fhe risk of serious

be reduced accidental

poisoning. concentration for 1liscellanec - .-jf camphor is External in all

A listing gf the

in order

of decreasing

submissions the

made to the Panel of

Drugs to 0.1 .

shows that percent.

concentration Tlthp

camphol:varies

from - G5.8 percent _ of i&.-l s

TABLE I..

J

,

.A...-.

.*---------

-_------ll

--__l-~c-~.-.

-

--

-----

Submission(J)
-_--_-

Camphor content

and vehicle
--

' ' 1',, Subrui ssion'*L"
--

Camphor content
--

and vehicle

-..__. ----

0

1. 11160225

65.8%, dressing 2. i'O60062
I.5.4%, ointment

3. 61.60136) 11160231) 4. I/160002 5,cf 1.#160225

10.8%, oil 7.4%, vehicle 6.58%, cream 6.0%, balm 7. #060051
5.78%, ointment not stated

6. 8160078

5.7%, ointment 8. #060040 9. /I160262 10. #160136 4.75%, ointment 4.4%, powder
.I

:,.57%, linament

11. 3060008 12. #060030 13. #060031
2.5%, ointment --.----

3.75%) 3,59%,

linament linament

3,0%, linament

.._,

15. if160058 16. #160005

1.6%, balm 1.6%, ointment 17. #060029 l.ii%, spray

18. #160004 19, #1601.74

1.48%, collodion
1.48%, ointment

20. R060050
21. lFO60054

l.ClB,

ointment ointment

l.OZ,

22. 8160036 23. bl.60016(3)

1. 0%, ointment
0.82x,

linament balm

24. #060009(3)

@.8"%,

linamcnt

0,8X,

‘ ‘ , I .: .

:~1G!m/G

0.6X,

cream

. .

28.cf8#060040 I c ,cf 27#160076 . 8160147 .cf1#160225 !. #160080 * . 3. i'i160093 14. /I160278 35. ? 36, 37. 35. #160059 #160008 lr'l.60013 #160030
0.4%,

0.5%,

balm

liquid cream cream lotion ..:ream powder liquid 'iquid tick itick .'otion

0.37X, 0.34%, 0.3%, 0.3%, 0.25%, 0.22%, 0.2%, O.l%, O.l%, O.l%,

0.3.%, ? oti.on O.l%, 39. 8160104 O.l%, O.l%, 40. 41. 8160213 11160019 O.l%, not :.pray trcam
: ?r.iOll

; 1l.m st:l r-ed

1) Submissions
'1 Submissions >

submitte! submittec!

to Panel t&j Panel

for for

Reviewing Reviewing:

Miscellaneous OTC Topical-

OTC External Analgesic Drugs.

Drugs.

conccnt~ion recommended --

of

cal~,phor.

This I .-. .__ is in

alno --

the conctntr ""-.

[:-ion of

cam* --

by Angle

1976 (Submission. .._ 160222). ----.- -cognizance in of the volume the safet; <.f a product of a product, and con-

In addition its concentration

to taking of

camphor

evaluating

sideration ingredient camphor. contain

has to he given

to the

effectiveness aid because of

of c mphor as a single a 111ique property of

or as a pharmaceutical All of the products a lethal

containing dose of

2.5 percent in the

cur more of camphor container

more than

camphor

in< ividual ha:

when ingested a beneficial applied fication mentarium

by a child pharmacological

and none of effect

the products due to of ict$

been shown to have content when

cam;'ior

externally. would not

Moreover, be removing available for

removal

the produc; preparat a patho:

; from

OTC classithe armafrom

any essential alleviating -.

ion from ogicl

of drugs

process

the human body. . In TABZE 1 there on Topical centration Panels, Analgesic about quite hoped this Analgesics of camphor, panelist and its are listed also those the submission, made to the Panel a high to both con-

as one of

submissions product

co' cains

one particular was asked

was SE‘ ::itted

to review for

the report possible Panel

'>y the Topical information

Panel

submissions

adds i.ional rated In

camphor differently

and the Topical than the what

Analgesic this Panel in the

( Tmphor products ilhis t :' the report way it is

proposes. conclusions

to resolve

differences the OTC Topical that

two Panels. on Camphor, and

Upon examining pp 234-243, erroneous it

Analgesic

Panel':

was found of

the poor

documentation conclusio:

of statements .: arrived

citations

references

made the

at in

the report ature opinion

uurelinble. in the

0n'i.y report.

uric

origin11 For basic

art iclc iriformatior: and over to arrive 80 -original pp I+Sl, 12-24-!G, in H.E.

Ci fit

liter-

was cited

at an articles a Review Morton. in of

on camphor

9 books

and compendia were cited

the scientific Antimicrobial Some of in

literature Properties of

on camphor, 2nd draft commission

of Ketones, the errors of

the details

and o .:-ission

are

set

forth

a MEMORANDUM dated

14 December External there

1978 to the voting Drug Products appears

~zcmbcrs of Advisory by the

Panel

on OTC Miscellaneous At this of safety to both are for panels.
ti.me

and FDA OTC Staff why the

same author. standards submitted There camphor,

to be no reason fc

same

camphor

can

not be applied

the camphor products

two prodlrcts spirits

(1)

camphorated

oil,

cont. Lining 10 pc 'cent
time

20 percent camphor, listed Formulary. subII that

and (2)

of camphor,

containing for a long

have been available in the current danger far

as OTC products of the U.S. their

h ,t are not .he Nat.ional

editions

Pharmacopoea and, should

and whil

Their mitted for

outweighs for

usefulness they for

they were not

to the Panel

evaluation, products

be p3 :ced in Category use con.aining more than

safety

as are other camphor. with the

external

2.5 percent Starting two products, ing 6.58

individual 65.8

products, percent

submissio:: camphor

160225 presents containcamphor that the proof camphor The and

one containing Only label

and the other s;:ecified

percent. but the

two active on a package

ingredients purchased

are

m-cresol, duct is

OTC st ztes

contains

thymol

iodide, aid

an antifungal .

agent.

Th:: purpose and .;ugenol.

a pharmaceutical

to detoxify

the m-cresol

camphor cent

forms

a complex

with

the

22.36

percent

O---CL-L::,I and 2.23 and (',31 percent 1938) that

perfree 1

m-cresol

so as to release Price

on1.y 1.6 percent stated

m-cresol, percent caused

respectively. saponatcd some burning on the skin cresol

(JAHA,111:1993--6, to about 0.S pr-'cent

(equivalent of

cresol) the microa brush, its soap in-

and anesthesia no more rapidly of

the skin than in

and rl !juced ,l:ith ,:t

organisms

scrubbing, the prod of the pharrna

and tiarm -dater. tended for ties the Other claims in purpose. it is

The presence While reducing

camphor the toxicity

defeats

: ective :)logical

ingredient activiof camphor. the

tissue

concomitantly

reducing and ar,algesic is practically

other

such as antimicrobial camphor-cresol details of of complex lack

activities. the same a. dat;> are p campho' discussed

The toxicity for pure

of adequate and antiseptic

or sufficient activities containing .-

LO support .:vided first

germicidal

on pp 47-62 draft 02-08-

the Evaluation

of Preparations

77 as amended 04-19-79. fiably be placed Submissions product, aromatic than a mixture oily in

The two products II for safety.

3ove can justi-

Category

160136, of 10.8

160208, percent

160218 and 160231 F camphor and 4.7 p 1 f

*tain scent oz,

to the phenol contains if

same in an more

solution.

7K The L

smallest

container,

dose of cam&r for a child ---the and the amount in/4 fl oz container -----.- would have in any other camphor Centers poisonings
Of thC

a lethal

or even an rrdult, ---___ ___ ___ be extreme

ingested, to

I*: dangerous ____

a household. caghor products and 292,

This product. --

product

causes more poise. -----..---were 5 -.-

'ngs of______ than ..____- humans _I_ )_.._-_ poisonings ;e Poison T-oduct. due to C0nt;ha.L Of the 292

During -- 1974 there to the RntSonal ------&J.-

reported --

Clearinoho.

or 53.,87 percent, product, --. due to all

were due to --this 23 or 7.87

due %o this

percent I_.-.--. 1%:7-e hospitalized. ______ prod11 r-s, 54 or 21.6 per-

250 ?o&onin@

other camphor --..-_

cent

were llospitalized.

7 Thus wllile --this product the camphor -----I_ is -.--..----- ..__----product most / -.-. -_-- --- :::ely

to cause po-ison___._.. is most

iw ,
likely

camp!lor

l.in?ament whicl~ -------

contains -- nc2nrl.y-.._____II___ l:~ch - ---. ..-I-_ .-_ - .___ twice a?:-: ..-. camphor (160222). These f ---.. .ures __: -oduct oj for

to require hospitalization ------l-~_I_I__I-y as the poisonings in 1975 and 1976: is more soluble

1974 are

concervative &markedly

reportedP1---"‘ to this due . on --- the order -I camphor-aromatic 4.75

increased-

increasing --I__ in the

27 to 342ercent ---* oil vehicle was

Phenol

7: 'neral per<

than .in water. brought 1.026 into percent

When the product contact phenol. with water,

containing the water one--fifth in

nt phenol

phase was of the p!

'ound to contain no1 went phase into the

Thus about

aqueous One study was found

please and four-fifths was made with that of 1:lOO 10 min.

remained

the cnmphcr -oil cells killed a 1:lOO

(160136). and it cells in in

the product of this it

and tissue

n culture \ (2 tissue 'i-ltltion

dilution If

the product represented is

an exposure the under aqueous those This function plex with

of phenol

phase,

l:lO,OOO,

conditions. and the is in

Proper

questionable that .controls were not in in 160225 ar.

hen01 was lethal uded in similar aid the in test. that the

product of

one described the role

camphor

of a pharmaceutic: By using ingredients _ contact _ with
the

to form of

a comcamphor inof

highly complexes

poisonous with the

substances. toxic active

lari I

amounts bind

to form activate the

and thus

the active ingredients

ingredients, can come in %

." J rge quantities I :iy with

active

decreased

harmful

effect. beneficial

Nothing the is for other

has been demonstrated poisonings cells.

for

tit-7

product each year - appears

but,

on

hand,

numerous to tissue

have been record,: II for safe'

and it justified

destructive this

Category

product.

doses have

for in

a child a household. rel-icf

and the There

largest is

available no evidence

amonnt -tr: too dangerous that Its the Ilroduct use might would

to give

temporary in

from

throat sense of

jrritations. security

be dangerous therapy 7.4 percent and in

conveying

a false

and causing

effective 160002,

submission Category II for safety, not to be sought. camphor. There is no evidence that camphor is an emollien:is helpful in eliminating chappi.ng of lips and skrin. desired produc=

or moisturizer The vehicle pharmacologic may provide

preparation action. than of

160078 may be providing The G percent camphor camphor in if in

the entire the marketed the product far

more

a lethal the presence for is

dose of of

was in,n,cc;ted.

The danger usefor

camphor

the product of

outwei.g:i-lr;any possible so Category II

fulness safety

the recommended a logical

purpose

the product

classification. in the ccncentratinn of 4..75 Itr‘ rcent in the pro-.

Camphor is duct is of described

present in

submission dose for

160262. a child

The camphor if ingested. following There

coni snt in a 1..5 oz jar TliJre is one report of an activity

more than a child

a toxic

having

a severe of

toxic

reaction

tl.:> ingestion brain

estimated for for

teaspoonful

the product.

was altci-,?d

at least

15 days as detected as stated on the

by electroencephalograms. label. are that it

The claims

the product,

<s a decongestant with nei.ther of

and relieves these ties

coughs

due to colds. properties

Camphor is (Merck Index).

creditcci

pharmacologic of the other

The phxmacologic

prcper-

ingredieats

are

as follows: *

Menthol Spirits

- topical of

antipruritic - solvent for oils, rubefacient, counterirritant

turpentine

Eucalyptus Cedar Myristic leaf oil

oil oil

-

local.

ant.isc’ ptiC,

expeCtOr~ll~t:

-- substitute - ingestion of

for large

oil

of lavender quantities prc- iuccs de1 i.rium, narcosis, death

Thymol

- antifungal of the presence of c,amphor in is obvious the p' 3duct that a clas! cannot be far of ex-

The purpose ascertained ceeds

readily.

In any case it usefulness which

.Lts danger Lfication

any intended II for

justifies

Category

safety. of is 4.4 percent not stated. of camphor It is the in not feet. a powder 1 rth known to Campho. for in 2 percent phenol in the

The purpose for a foot powder

>c effective

treatment in Category

of epidcrmatophytosis II for effectiveness

has been placed 'resting I.15 the feet. form

in preparations a group lips. of products

Submission recommended is essentially mint for

160055 covers treating the

oz stick

chapped for the

The composit agent is a

'n of each product camphor, ;.6 percent cherry, in one ingredient agents; II

same except While is other or

a flavoring camphor amount, it

grape, of

or orange. which in

content is not

the products, is replaced grape, of

a safe but

.ecessary :voring

as it cherry, for

similar

products I for

by f' safe for t

mint

orange.

Category

$. and Category . 'ie intended

efficacy

camphor

as an active submission,

ingredient 160126,

use of

the product. with lesser

A revised amount of

covers

Y same product

camphor. of the product are listed described as active in ingredi 16 705 contains .Its. 16

The 1 oz package ingredients, 7 of which

Camphor is

present dose if pain

in

the

concentration The label ointment

of

1.6 pcrc:t:11t wh-i CIl c.01:, rl rel)resent the product suitable to bc an ideal as an 2 lplication ic action

a toxic antiseptic to boils. or that was

ingested.

states

relieving is

particularly that

No evidence it is

produced in 10, the

the product of boils. that tests

has antise:.

efficacious

treatment

When ti-t A submission arrangemits

made in January for
the

1974 it of animal

was stated safety

had been made would be subis

performance

and the r(, :ults 1.

mitted presented material ratio campllor free

upon completion. that tested of camphor complexing the product in vitro to phenol with II

No results

have been receive is of the
same

No evidence

as marketed for of the

composition .a1 growth. in

as the The the

inhibition

of bactel4 to

approximately

1 m: -.ljt result

the phenol for safety

and thereby

reduc? II

:g the amount of -or efficacy are

phenol. for

Category camphor. percent

and Category

recommended The 1.48 in submission in

camphor a safe

in

the 0.31

fl

oz of

tl

product :amphor

described has been of

160004 is II for

amount of camphor by the Panel

but in

placed warts.

Category

efficacy

t? 2 treatment

No justification in the ointment

is described

given in

for

the presence 160174. ring

of 1, ,'a3 percent The lxroduct worm, l.>lief is

camphor recom-

submission of the feet,

mended for of the

epidcrmophytosis and genitals, poisoning, than

of itching burns, antiacid and The

rectum ivy action acid

and itching etc.

due to eczem. i superficial has a muci stronger

abrasions, pruritic benzoic

The phenol

camphor

and the chlorothymol, antifungal action

s licylic th

have much stronger

n camphor.

1.I.
I

,

.

I

ratjo

Of

CUiilpllOl:

to

pl,enctI

0lI 1. 5 to

1 raises

tire po:;sibility tile of shoul;i .lmount

of campllor of free is phenol. safe as

complexing While but

with

the phenol of camphor

and thereby in

reducing

the amount as an antifungal II for

the 1 oz quantity agent it

the product be classified

and antipruritic

Category

efficacy. of 1 percent the amount of in of camphor in the 0.42 Camphor Phenol It was on the of has

At the and 0.14 is not

concentration of

oz packages

the product against

described the virus

16C'.06 is co'd

safe.

known to be effective analgesic that action 0.4 tissue

sores.

a stronger not

and antiviral percent cells. phenol

action

tha.? camphor. .iral action

demonstrated virus within

has an anti of

herpes 2.5

In the ratio with II .for phenol

L.amphor to phenol a:.d thereby reducing

to 1 the

camphor free

may be complexing Category

the amount of camphor.

phenol.

effi.cacy

-is recommended

j?or

In submission present tion It in is the it in the

160016

camphor

is

listed 0.82

as an ac'ive percent.

ingredient

but

concentration

of about

Xt this

concentraactivity.

has never not mentioned

been known to have analgesic in the Oil list of of active Camphor. The 4 fl doses of

or an -iseptic but it

ingredient:.

is

stated

label

to contain very toxic

Camphor and 3il

of Camphor are of In

each rated the view in linament of

chemicals. several containing Category toxic

oz and 8 Sl oz containers camphor amount until 1.2 ingested. of Oil adequate

contain

the product

an unspecified II for safety

of Camphor data are

addition

to camphor,

provided. Submission 160126, dated May -7, 1975, covers a I-,roup of products in

0.15 recent states

oz stick

form

recommended thau 160058 of

for

treaiing

chapped date Janus:

5 ips. ,: 10,

It

is

a more and as

submission the

(submission

1974)

concentration and perfume ingested

camphor

to be 0.8 percent The total amount medic-in;,

and is

present

a flavoring is safe if safety. 'In percent

substance. is

IT camphor present ! action. Category

and no claim

made for

I for

the antiseptic camphor for is

solution present

described

in

submiss

x .or

lG0084

the 0.649 alcohol.

as an official alcohol is

denaturant camphor/: be reduce. es

the ethyl alcohol,

One formula Formula product also 38-R.

denatured

10 lbs could oil

_)O gals

The amount of 1 lb

camphor

by 1 lb since bntial oils

the

contains

of peppermint

and other 30-B.

which 40.26

are official ethanol quantities ingested. affecting a denaturant

denaturants

in Formula

The ; :oduct Th< a a 4-l/4 !:?thal Ither \pyl

contains oz and all

percent larger phor , if without used,

by wt and requires of It the product might

a denaturant. contain more than to select If It

dose of camdenaturant alcohol was to Price

be possible the product.

the aroma of would

isop might

not be necessary. a mixture reported of ethanol

‘ worthwhile e. canal which g G.cidal. I for )ry II ! its for ethyl

investigate (JAMA,

the use of 1938)

and n-pr

111:1993-6, product content boric 0.649

to be powerfully Category content II for I for

This alcohol for for its its

has been rated and for its

safe,

benzoic Categoty content.

and Cats safety

safety

acid

content. camphor

1s been proposed

percent

The product for the claims

has been rated that the utilized camphor

Category provides

II

for

effi analg

'ICY for .-ic

camphor

local

and antipruritic

properties

and is

as a rubefacicnt.

3.3

The camphor 1 oz package tent, tains tain under liquid cient could 0.4

conttrkt,

0.6

percent, in

is

less

that) 160076. the lir!of for of
f.he

:

toxic

dose in

the con-

of cream described in the 6 fl

submission of

The camphor 1-d product l ,jntents ~:y could

percent,

oz package

concon-

a lethal a toxic

dose of dose, if

camphor ingested. However,

and a porti-on Category if II

might

saf:

be logical for the

such conditions. preparation

the size the

the .; ,;ckage :ould

was reduced to health I for for

to 60 ml,

camphor-

not be suffithe cream,

to be hazardous be rated No reasons Category

and the liquid safety. designating product until but data

produc 31, like

are given

camphor not arc in

an ::ctive the other

ingredient liquid prothe

in

the

cream and in Category II

one liquid for efficacy in in

duct.

prese,

.cd justifying

requirement Product 02 quantities. of tion

of camphor described It is

the products. submission 160147 is markrt; that a person -d in 1 lb and 6 sufficient

inconceivable a toxic 0.37 the is

wo: Yd ingest si.

the material of camphor

to obtain is only one of sunburn" not accomplish

dose of camphor Category "cools

'e the concentrasafety ;tes in regard

percent. claims

I fc:.

to camphor. pain

Only

and allev‘ nature and of

the minor amount of clove to reIII for oil

of ordinary

of a medical that in

,:he small F:enthol, ‘ :le phenol Category

camphor would and phenol.

the presence with

The camphor might of free phenol

complex in

some of

duce the quantity efficacy in regard of

the preparation. camphor. in in the unit pat'

to the camphor oz,

ingredient contained

The amount Calamine not Cream,

.:gc of Obtundia so small if as

0.11

described dose for

submission

160 25 is .:hild,

to constitute

a toxic

even the smallest

ingested.

Category

1 for

sarety

in

re;ard

to

c:mjJ~t~~r

%n

th-i ': 1~7 *duct.
cff_ic

~lWeV?r,

the product for lack of

has been cla ssificd evidence to support described a mild of lotion in

Categc.~ry I'r the in claims. submission

for

cy and labeling

The two products percent individual cannot camphor carton be determined for

1602380 -zch contain action. '! 2 quantity

0.3 in the

counterirritant is not stated

so t11e ST':? y of This II for is

the product as of

regard

to camphor. Category

I, t: important ty because

the products their zirconium

have been classified content. described powder foot in

sa;

The product camphor for is a foot in

submission

lG0093

cont::'r:ing

0.25

percent II

and camphor has been placed

II Category

efficacy

preparations. in submission 160278 coat: .- denaturants is 0.74 -oz whit!? a child in so ils 0.22 percent

The product each of camphor

described and menthol quantity is not

as official marketed

f r the alcohol. contains he product o camphor. about 45

The maximum single mg camphor. be given cacy of This

a toxic

dose for safety in this

has to Effi-

a rating camphor is

of Category not

I for

regard

applicable

product. in would submis:: not on 160059 cona toxic camphor present it would

The 3 fl tains

oz of

the product g camphor.

described This safety for

an estimat_ed0.180 a child,

cc .stitute o the it :ation 'lites, is

dose for component. in the

so Category II for

I for efficacy percent. the

in regard camphor s:inr

Category

concentration

of 0.2 effect in

At that

conccn:

have no beneficial heat for rash, which cold

treatment p-oison ivy,

of insect chafing it as

acne pimples, foot

sores,

dandruff, is

-nd athlete's :n active

the product

recommended.

Listing

15

ingredient exclusion Category II

might

give

a fnlne

sense

of r.c?l.iance on li 13 product The product acid ha: been rated

to the

of more effective for efficacy present for

therapy. the boric

compone::' u in t :2 concentration '1 submission 1% ighing II for of 160008.

Camphor is 0.1 percent There would Category since in

as an active a stick

ingredient form,

the product, than

described the stick Categor that

be less safety

3 mg camphor in

0.1 oz. efficacy would dry

I for

in regard to prove

to camphor. that

data

are lacking effect healing

camphor in instant

concentration :)f chapped,

have a beneficial lips; blisters, antibacterial pected promote

in producing

relief

and ease the discomfort lips due to slln or wind The benzocaine action. in

of co J sores, burn.

fever has no be ex-

and cracked action

<'he product

in vitro.

and p ,-.nol would

to produce

a slight is

analgesic

The camphor content cribed labels in submission

0.1 percent Volume of

the outsi.

e of the stick 5 not stated

desas no

160013.

the product January 1:

are provided. that

Date of submission,

1974. :m animal

The comsafety The on the

pany stated tests

arrangements of the tests that

have been made to perf will be submitted search treatment is of upo bein cold

and results stated

completion. performed

company also ingredients of the study

a literature in the

as medicaments will

,-res and the results

be submitted search and labeling

upon completion.

Res !.ts of the safety Category II for

tests safety,

and literature efficacy There are

have not been submitted. for lack of data. in submissio

three

products

described

160030, However, <,ent for

each conthe recomexternal

taining

0.1 percent

camphor as an active of camphor is usually

ingredient. 1 to 3 pc

mended concentration

2

b

4

application any
phnrmacologic

so it

is

doubttul. If

li f 0. L pcrccnt it js present

cClnC;C?lli.

,lti.on

would

have

acti.on.

in

the p> oduct it f :lould

as a phnrmabe so stated. than a 1

ceuticnl The entire toxic

aid,

such as a perfume of the largest

or prescrvtlt:ive, container T for safety zirconium

contents

represc,.i:s in

less

dose of the I for

camphor. Ziradryl safety

Category Lotion

re:;; cd to camphor. oxid and was classified 1.y III for efficacy

However, Category in regard

contains

in regard content. described

to zirconium.

Catcgr

to camphor

The two products percent container the

in

submission ingredients. contain I for for

160104

:>ach contain of

0.1 the so

camphor as one of is 4 fl oz which would

the active would not

1'1 2 volume tose of regard

a toxic safety in

camphor to

classification is

be Category as an aid

camphor.

The product of skin; tact
*

recommended of itching

cooling, in oak, skin

so: .hing di, jrders insect

and healing such bites, usually the proit actibe so in is as con-

relief

and discomfort ivy, poison

dermatitis rash,

due to poison chafing for topical only the l/10

sumac,

diaper

and eczema. application to l/30 content of

The concentration is 1 to 3 percen recon:

! E camphor L Since

recommended duct contains if If

the usually intended

:ndcd

dose,

doubtful vity. stated regard presence

camphor is

has the

pha. sacological aid II it ior should efficacy its

camphor

present for its

as a pharmaceutical presence. of data Category to support

and the reason to camphor in

due to lack

a rr ison for

the product. weighing 4.26 g described in submis Len 160213 contains ,?f the package ate Category I for

The product 0.1 percent not

camphor. contain

Therefore,

would

a toxic

the entire contents e dose of camphor and would

1.3

safety relieve cold.

in

regard

to camphor. sore l.ips

The intended

purposes
c?gain:,

c.

the balm
> sun,

are

to

dry,

chapped, is

and to protect tllat camphor the claims in

wind

and of

No evidence will

presented

the the

c LSicentration zoduct. 1. in

0.1 percent II for

accomplish for camphor l/6

any of for lack

of

Category

efficacy The product

of supportive stick form

d:,

weighing camphor

oz and in

dr, :ribed

submisis .

s-ion '160019 lists intended of cacy in This ointment dients, camphor of for the

as one of

the ingredients. chapped lips. II Thi;for

ihe product oncentration .nfety

treating ingredients
to

dry, cracked, not is /specified. for lack

Category of data. should

and effi-

regard

camphor

paragraph, described 2.5 percent in a 1 lb jar in

rightfully, submission

be paragraph

on page 8. ingre-

The

160106 contains, percent contains is boric

amc ., other a<' '. .ic

camphor of

and 7.75

The amount of doses, if some

the ointment There

many t t11 o: re. Cat.

the product

was ingested. to the inhibition

no evidence growth II is

camphor that the

contriproduct, safety safety

butesanything itself, in in regard regard

of bacterial Category

has antiseptic to camphor. to the boric

properties. The product acid

:.mlended for ory II for

has been rated

component.

In

evaluating

some of into

the

canphor-containing combinatic

ci!-: ;; products

it

has

been necessary other tures, chemical each' other. with freeing aqueous complex some of drugs. wi.th

to take

consideration in are forming eutectic

:j of camphor with or complex nd not mix-

Camphor is other drugs

unique which is, in

complexes mixtures

new stable in .

compounds.

'I'hat

two or more substances contact with drug water going the c into

nre soluble

Upon coming

.;lplex may dissotiiate : !,lution luble and possibly drug in the the

the more water-soluble the camphor.

some of phase is

As more of more of

the water-: 1,

dissipated,

the drug will the (JAPA, a complex the molt

liberated

from

to maintain

an equilibrium studies of the

between by Francis two drugs

aquec? -; and camphor phases. 33': c: .?9-40. 1941) indi-

'Physical cated that in

chemical a mixture of phenol are basis the

one mole of camphor ilar -, this of 1:6 weiglits of

and one mole camphor that

predominated. 152.23 the

Since

and phenol

and 94.11, are

respective? in the rat< and predc

indicates to 1, resa complex Since the

on a weight In of

two drugs a mixture

pectively. of two moles

case of

of camphor cresol this is that

-cresol, Inates. that

camphor

and one mole of is 108.13

molecular basis It tile is

weight ratio

of m-cresol of camphor

indicatt 2.81 to 1.

on a weight

to m-cresol

important mixture that in the is

to keep in mind depends in the

the pharm?

:llogical

activity

of a eutectic soluble of the In imately drug drug the

upon the

concentratior and not
~1;’

>.,f the waterT the concentration

aqueous

phase

camphor phase. mixture, the m; as ture has approxIii -the

case of a camphor-cresol for

the. same toxicity

laboratory

animals

.zmphor .

1.9
. I .

case .-----.---_--_.. of the cnnlp!lo~---phcnon mixture, the toxicit y ____-___ --___ll__---_.__l_ cf -. : he mixture .-_--b---------.1-- for laboratory .~,_I_.-_-poisoning ---2 animals .--- _._. ._.-_- .~ tletcrmir~eo ._------.----.-... IKE: not 11een ~_ _ ._-. -. but .it in humans than --__-. cz _:ses more cases of

any other -11OTC crimphor-cent:].-..- [ning compound. .-~. -- -. -__--there ._----__-.YLCI- listic is a sync;rtiaction. -.. 1--1--.action of

One contributing ------~~-~-_------_--._factor may be that -camphor -----l__l_ and phenol

in proclucjncr a _-_-_ toxic ______. _-iJ

'i' ~. +s was demonstrated 0.3 for r: camphor/ dogs given

by Bond and HaaS (PAPA, lA:llS-20. 1925) WI---r___---l_-

who report-c, - !I.- that -_-.-, oraJ.ly _.~-

kg body wt and 0.3 ml. phcnol/kp -.L___----- wt were not toi:'I --1_-__--. cI_-.----- -_____ body when g-iven ----"---___ togetllcr, individually one-2 eiven but trhen both l_---l___. immediatelv ,.--?-.------L--- after in the 160--drugs in

theg!;- "__ amounts were th<:- .-~--cc..--.L dons died that . ere submitted attraction and might etc.

the other, series

Many of the

the products

to' to readily or

Panel. are aromatic The containers on the drawers
the

or flavored are often

so as to be a pos,‘ ible attractive stands, and c- all dress! or in

children. be left in the

top of

of dressers, such pTeces of

night

~2 tables,

furniture,

a :,:oman's

handbag.

Many of of

products A child it. from

-are used on children may be attracted reasons

so may be to a product

‘ the environment il or having been to proiq

children. with children

treated tect mobile

For various

precautions OTC drugs.

zti .t be taken & weirh .---L

camphor-containing at 2 yrs of

.;l,ming a child s about _

and inquisitive a toxic apparent for that

age when it is about

12 kg and it is

byassuming -__readily
may

dose of

carnqhor . ..d

0.030 2, ..I-- then L.2, containin 0.360

the amount ___-

of a drug

g camphor

be toxic

a child. a rule of thumb that --of volume of drug: ._ ,.. in less liost individual than 0.360 g

By applying container in order

- X percent for

concentration to -.-- be safe

camnhor must --. he + for an OTC drufr. __---\I arc srlfe. --~-_

the product less than

of t-he drugs

conta:ining

2.5 pcrcL=nt

camphor

( i the submissions

.

less -containing -2.--.------- than 2.5 percent - camphor only..-_four - ----. -._-. __ ____._ __._ __-----I-..-- .--_-.-dose of .-_I I canqjhor for --*-----contains 0.448 a small _.-__._ _-- .-.-" child. If The 1 oz quanti;

)nt-ain 3 toxic .,-_.-. --_l_ I of product 160005

g camphor. concentration the

the volume of

of the pr-CP :ct was reduced i from
L

to 3/4 oz or the to 1.25 of percent

camphor was reduc be at a safe might a child
1cc.w:

1.6 percent Oil

campfior would in

The rosin,

Cade and ichthamol but

the product knows what

make the will

.;roduct

unappealing

to a child The Oil individual tent label

one never

ea' . an

of Turpentine from swallowing

and arnzonia might the li:?;lment

be enc" ,h to discourage in 160016. stated

descri.bed as tile

The conon the

of camphor needs to be investigated differ The 4.25 from the submitted list

COD !ilt.s

of ingredients. of prodcct the capacity zi.t mig 16C ,4 contain : : official : bc possible 1 _ a combination many denaturto of

to 32 fl doses

oz quantities of camphor in

potentially ant for

toxic the alcohol.

To eliminate denaturant,

the danger a different

select the two. If from sibly

a different

alcohol

the volume oz to 3 fl

of

th e product oz the entire dose but

in

submission

16C

G was reduced ttle would pcsmight

6 fl

contents the tannic

of the . acid i

constitute

a toxic

the product

discourage

ingesting

the product. content is
10~7

Where the camphor uated individllally flexible

each product

: teds to be eval9 a safe evaluation make flexible e and sold in range. and 2

in order

to keep the camphor wit: was not submitted aid ns>chi. f% t

For example, percent collodion.

collodion

camphor is

needed as a pharmaceutical is usually employed

The product

?I

quantities is safe.

of 0.5

fl

oz or less.

In

this

amount

th(,

camphor

content

The submitted should great Product ingredients cause of the present camphor

products

containing for

2.5 percent categorization

c‘ more of r 1 ::cnuse of

camphor the action. list of

no great cont.ent

problem and/or lack

of effective tested product of

phar-.-.;?c:ological and the 160136 r;ubmitted is the

160225 has been inadequately is not a true statement, of cases for

leading and product No evi6 percent camphor It

annual

hundreds

camphor

po.; <oning tivcness.

160002 is dence is

supported presented

by no tests in submission sore lips.

safety

and effc;

160078 for No evidence a beneficial of the throat without is needed

the necl ssity is effect prc: ti

of

camphor in is

for

treating

;?nted that the product. < which ,~g the

product

160262 contributes for congestion sense that

recommended

and the correctin prc of a us the OTC

may give illness. No No

the patient evidence person is

a false presented

of relief camphor would were

,-~ct 160106. drug

needing

medication products aid

be deprived removed from

5111
if the When used camphor does ~:i.ssion . series. contain the in the All of methyl danger

above mentioned as a pharmaceutical not fulfill the

7rket. :, the ::cts.

in

some of drug

the above prods for OTC pro

combination

policy

It appears to be possible to categorize the su series 060---/on the same basis as submissions in the 160the submissions contain also camphor contains in and all mustard the products except oil.

one L lso Here ;igain

salicylate of

and'one of

the presence

camphor

outweigh

any possible

useful-ness.

. I I ” .

_------.-. Submission L-1_160225
NO.

TABI,I: 2 e s,,1y; zrj&&; Camphor cont. -- -__-__-_-.65.8%

u'd,a&,,

II. i lassification Sri. cty Efficacy - ..---. -Page 596 II 596 13 6,7,8 8 8 899 17 II II II II II II III III III II II III II 9 9,lO 10 10,ll 11 11 11,12 12 12 13 13 13 5,6,13 14 14 N.A. II II II III II II II 14 14 15 15 15,16 16 16,17 17

a

Volume of prnduct Toxic -__ --------.--__--. 4 fl oz, 3-112 0% 16 oz, l-S/4 0.11 oz 4,2,1 7,2.5,1 1.5 07, 1.5 oz 16 oz -__--

6.5% 0.34% 160136) 160231) 160002 160078 160262 160106 160056 160005 160004 160174 160096 160016 160126 lGOO84 160076 160147 160225 160080 160093 160278 160059 160008 160013 160030 160104 160213 16OOi9 - 10.8% 7.4% 6.0% 4.75% 2.5% 1.6% 1.6% 1.48% 1.43% 1.0% 0.82% 0.8% 0.649% 0.6% 0.4% 0.37% 0.34% 0.3% 0.25% 0.22% 0.2% O.l.% 0.1% 0.1% 0.1% O.l.% ?

02,

oz oz

YE!S Yes Yes Yes Yes No Yet3 No No oz No Yes No oz NO
k&S

0.15 02 1 oz 0.31 oz 1 oz 0.42,0.14 4,s fl 0.15 oz 5/8,1 fl 07, 4-l/4,10,16,32 1 oz 6 fl 07, 6 oz, 1 lb 0.11 02 ? and 1.25 02 3 02 0.74 fl 3 fl ? 6 fl 4 fl l/G oz 02 oz oz 0.1 oz oz oz

No
Yes

No No No No No No No No No No No ?

4.26 grams .

23

---_

discourage_it is

__--._

be.i.neken

orally,

and providing

I10

1,

licinal

activity

claimed____for -_.

the ____ inuedient --_-/ camilhor I_ _"_.

e ;:rj
ynJ:rr

.,,, c f,‘ .asturl);itron , .: 2n of Pro;:rarns
and A

M of Childhood-G De\rcned To Incrcascr
F. L'i'lllI?illr-

r+,kc r3)
the Protectron hflnf:,nts’ in Cars--K S.

. ,

, . ,,

_ .,~,,~ous Adrninistrstron of Live Attenuated nleasles Vaccine \Yrth DIP Vaccine-A. .,* ;,:ctjcnrr et al. in the First 48 Hours of Life-R Hodgkinson et al -.. 1~1 fictrrobehavior *,born Inf-.nts-L 0 I rlren et al , o:,5et I~aemophiif~s Sepsis in rdckb Gactrrernia rrr Pedratrrc P;zfrc~nts-K f. fld\*:ards et al. . ‘ .,.l‘ : 1 rcr aerogenes ., rsed tieart Rate Varratron in Deccrebratron Syndrome--I’ . Kcro et al. -:,-some Damage in Infants and Children After Cardiac Catheterization and ~r,Ciocardiogr.,pt~y-F. H Adams et al ..,cular Systolrc Trrne Inter\‘ als in Neonates-H Hallrday et al. A Serwer et al. .,:, r,lar Tschyarrh>*thrnia Due to Cnrdra, r Sarcoiciosis-G. JJ;:nif Indrrect Blood Fressure Measurement Techniques in Children-R. F. Reder

ti a1 2 .‘ Concentration T\ of Homemade Baby Foods--C. 14 Kerr, Jr., et al . -;,rrtral:ir: Retrnopatily in a Patient \Yith Cystic Frbrosis-M. t. firmsza et al. ,..rjo,lic Dragnosis of Gynecoiogic Dtsorders in Chilcren-J. 0. tH;rller et al. -,-~cto-rc>~l Easis of tiyperkioesis Treated \?lrth hlcth~lphenidate--hl. N. Shouse and J f. Lubar for Chronic Childhood Asthma-T. Bell and J. Thecphyliine Th erzpy .,*,.acd.Rerease f: <ICY Psychiatric Consultation in Pediztrics--M LFWIS .I ILcmolytic Disease--W. P Kanto, .)I-, et al.

AL ARTICLES Policy Issues in lrnproving Child Health Services-L. B. Schorr !h Care for Underprivileged Caiifornia indrans-T. A. nlontgamcry r~:.~! Arusc: The 1977 C. Anderson Aldrich Lecture-C. H. Kempe :S’ hTRlCS FOR THE CLiNICIAN ‘ .*.rrtrtai Cel!u!~;is in Children-R. M. Barkrn et al. d-:!h Tests in Pediatric Gastrointestinal Disorders-R. “,‘ irIiCAN ACADEMY OF PEDIATRICS -“ccl of k?edication During Labor and
LJrug:5

G. Barr

et al.

* :

Delivery

on Infant

Outcome-Committee

on

:

A-Wror: Who Needs It?-Commrttce on Drugs ‘ rn Breast Milk-Cornrnrttee 2% on Envrronmental ’‘ c-~rlnrm!ttee on Nutrrtron ‘ **J!mcnt of’ Congenita1 Hypothyroidism-Committee

Hazards on Drugs

i’ : I ,

i 1

“ *LRfEfxE ‘ AND REASON--BRIEFLY RECORDED ‘ -:,rrfred Technique . for Tympanocentesis-S. L. Kaplan and R. D. Feigin >. ’ ~rcrduodcnaf Atresia (Diaphragm Type)-H. G. Mrshatany et al. .‘ c Adcnornatoid s!‘ Malformation of the Lung Associated With Prune Belly-S. t*.‘ rrson et al. ,‘ ltNTARtES ~:r’ ‘ crng Research in Otfrcc Practice--W. B. Carey flurried-out f,iissronary-ti. tf. Work and Child Psychiatry-f?.J.ti I’ d~lte-fi. I. fcrribloorn and lfealtti tducatron-I B. PleSS ‘ f’ .1l rogr;frir for tndi::c*nt fIrccjicaily Disjblcd Chrtdren-i-f.

K.

W. S. Powers,

JI

PCI)lACJ 62(3)

pp. 277442

(!371?)

.

Camphor:

VJho

Needs

IE?

.I of

he ol~tnincd by an indircrt the same segmental CSS !~caI~se of these actions, 111115 it\ $)rna and tra(lition, camphor i\ InitIti-ingrctlie~~t lirrimcntx fnr 9’ ,lief of “chest congestion” ant1 i’ iitse preparations contain fr0111 i>IrOr.
;ili\)I ii1

Toxicn. CampImr ix i.c., cer-rj inxic. letI1al dost: of : gnl gentr-nliy adult (TaI,k). ingested witIr

cy

~~l,rssified as a class IV chemiwl, !rbslmce, with a probal)le Ii~tt~r:~rr ; IO 500 mg/kg.i The ingestion of 2 rodlices dangerous effects in a11 !t!lough 42 gun (1.5 oz) have twci~ i.covery,’ and 0.7 to 1.0 gm (1 t\I) cmphol *Ited :l) has proven fatal in children. \i!ith rni!ti ~~Oi~OliiIlg, gastrointestinal tr,rcl symptoms art‘ iore corrinlon iiian neurologic, .?ilt! inclridr ixit, ;xr of the mouth, throat, d stOIll3ch. \‘ Oi, I ing may be the only symptom, or it may prcce or follow other symptoms. SyrrrIrtams of intr ‘ cation following ingestion 112x:. oxirrred \,it .n 5 15 minrrtes, but may Ix* clelaved up tc <everal hours if food is present in the stoniacIi : : interfere With absorption. Scvrrl poisoning is f .tracterizeil by convulsions, ~?Ilic II may be ~II;! .\rated by periods of apnea :111ti ,xs)‘ stole. I’ ok: :)nvuIsive depression of the CS.‘ follows Stin11 lion.’ Neurorial necrosis has Irrc~rr reported in 1 .rnan fatalities, and similar lcsi~rir~ have been p : ,li~ced in mice.! Fatty degemxrtinrr of the liver ;, I kidney may also occur.”

to
piS<Jnill$i

Clinic f

Iieports

Reports of :;rmplror

have

ap]l~‘ ~i :II~‘

Conclusions 1. Ca1i1plror
role in scientific-

1,:1s

‘ 10

cstnl,lished,

tlmlpelJtic

1n*:,‘ icine.

potent, serimis toxicologic 2. CampI~or 11ac, actions; the itlgmti( : of relatively small alll0~intS
~:i,xs pJ-rwcIl fatnl. 2.c(‘ . roll be t

3.
most

Alfll(l!l~$

COIllli-lOi>
(29 i~~h;tl,itio~i.

‘ Clltitl oral ingestion is tile : of intoxication, significant
~sorlxxi perc~itxnco~lsiy and

qilantities via

4. l’ J-arl\plxw~t~~
ktns.

transfer

may

be

toxic

to

the

>;I, in particlllar. is the worst 5. cmlp!lc~r3tf::~ ;nI ingestions, because it is offc:ncfcr- in accidf of over-the-cotInter mistaken for ;i aricty ingested b/v prodricts and is ; ,o accidentally toddlers.

6. As long

prod~wts as f ;n~pllor-containing i-ketcyl, pediatricians ShotlId :I;m;;ers bf camphor-containiDJIIC, especially caml)horated
COh~XlIT-I-EE 09

DRLKS

AMERICAN C,c

DEMY

OF PEDIATRICS

405

ABSTRACT

.

,VAY

31.

:

TIOriAL

CLEARINGHOUSE'-FOR

POISON

POI';@N cf?:: COtiTROi CEtiTEr.*

:SE REPGRT SUMM4F'Y
>A DUEEkiJ OF DRUGS, DI!IISiON OF POISON _I<z 3 ) L

CATEGORY 15: CAMPHOR PRODUCTS PEOC!JCT : ALL PRODUCTS :;!!:TI:l AGE CATEGORY: ALL AGES

ALL INCIDENTS . . TOXIC~‘ u sIGfwsumFio~lS FEVER . . . . . . . AT,?XIA ., ., . . L!u':ls LElWR&':::: CONVULSICNS . i?ASit DYSkA'::::: HYPUTENSION . CYA!IDSIS
FKE’ s:YhOEiIA

4,956 1,185 895 16 13 40 26 1’ 17 2: 5 21 11 3 371 389 552

431 133 109 2 3 209 26

557 162 113 3 3 1; 15 1

530 158 112

542 i60 125 : 4 25 20 1 7 3 1 44 56 77

653 150 119

-

583 125 92

1’ 0 14
19 1 4 2 2 50 2; 2

:
4

cor:,q . . . . . . . .
. . . .
. . .

:
3 1

:
2 36 5:

GI TRACT . . . . CTHER SIGNS . HOSPITALIZED . FATAL . ...* . . . VICTIM AGES Viii:CR 5YO . . . . : 5Y 0 /'<tlD OV Et? AGE UNSPECIFIiD !,ICTIM SEX ?:4?E . . . . . . . . . . FEMALE SEX ut;s&iiiiD NATURF OF INCIDENT r&DENT X!;GESTIri' : : : :
t, (1 :: 3 7 )I>, ; c E : SilXCII~E ,j +J ‘ ;, E J

: :f;
74

5: 52
89 398 107 52 231 217 109 ETC . 509 ‘ 509 2 14 8 24 161 297 294 263 27 21 494 4 94 13 1; 415 79 36 256 205 69

1 i : 4: 52 .--. 23

3,875 666 412 2,374 1,915 667 ROUTE, MANNER, 4,548 4,541
‘ K

315 82 34 209 156 56 INTENT, 402 402 14 15 129 213 211 220 13 7

401 74 67 259 223 61 486 486 I 16 2 37 224 274 356 186

549 59 45 340 231 82 625 625 10 1: ‘ 258 344 460 193 22 16

467 70 46 2:: 218 71
559 537

7

. . . . . . .

1Oi 2:: 1,782 2,568 3,332 1,574

5 3: 232 278 427 156

.

OTti!iR MANNER . . UNKtiOL~!N . . . . . . FROFESSIONAL . . LAY PERSON . . . . TYPE DF CASE TELEfllOtiE . . . . . TREATED . . . . . . . OTftER CIIILDREN . ItiVDLVED ,,a... TREATED I......

2 15 5 t-6 295 429 628 177

PEESGElCONTACTINGPOISON CENTER

i77
299 306 224

. *

144
95

10
7

10
6

:I:

.

USE AtiD ' I, SY? CIF If'tCAC ~'3?fEi? SULF. T,1z-CESSFUL i'h?!lCCESSFUi':

OF EMESIS, LAVAGE 1,252 . . . 8

106 3 58 8:

153

1 83 4 94 143 239 35 7 i; 7

113 1 54 i65

121 1

134

01 L1
107

. Li\~AGED . . . . . .

645 55 5S6

8:

3 99

79 8 74 140 309 24 4 71 83 4

69 5 43 88 207 25
12 16076

7 54

SO'JPCESOF INFORMATION USED BY POISON CENTER 154 ijOCKS . . . . . . * . . 1,030 1I'cpCC CARDS . . . 2,005 161 PR'JPUCT LABEL . 22s 28 Pi, 'JUiACT'JREf? F;:E'!ICUS K:;!JL':b 6;;: 4: 40 OliiER SOURCE . . 743 1jOT AVAILAi3LE . 66 10
PACKAGING cL9S'JZE S?,!-ETY INFORMATION INFO CAP . . .

188 186 46

55 38
17 6 44 24 25

132 273 25 2 53 62 10

112 321 ?i 10; 165 4
: c .; id i 7I#‘ : 6

6

:;I:I:-SAFETY . . . G?E:;

730 424
350 OR TRANSFERRED 367 18

147

16
118

CLOSE~~:::::~:: C?!GI!JAL CONTAINER r;!ICIll~P,L iF:h8SFEERib':: is:", ;: 1:ING LABEL yF ,s . . . . . . . . . .
;:‘ i

E
47 3 114 52 31 14

lE? 53
43 17 4 86 35
12

1::

66:
10 92 34 4 4

27 65 35
51

32 125 64 64 2
114

168
8

121 3
61

1 72 21 :

,.

667 222
SITE

22

27
:

CO~ii~itii~'~if%~GE USUAL PLACE . . iiOT USUAL . . . . X T3X3C E:D?T = CASES PREPARED

244
100 WITH

116 37 SIGNS AND SYPIPTOMS,
Ftl.D. (HFD240)

78 37

5

REt'ORTED "UY i-ihRK I

HOSPITALIZATION,

OR DEATH

FObJ,

r?LY

01,

d I)
,b

NATIONAL

CLEARINGHOUSE PRODUCTS PROD9CTS UNDER 5Y0

FOR POISON

POISON COh,.. CONTROL CENTERS

a ,a,1973 415 iO6
70

CASE REPORT SUPlflARY (FDA BUREAU OF DRUGS,

DIVISION

OF POISON

CONTROL,

tiFD24G

CATEG9RY 15: CArlPtlOR f'ECI3UCT ALL ;!ICTI:l AGE CATEGORY: __-----

ALL YEARS 1971 ----------------------------------------------------------------------~-----. .
3,878

1972
398 102 65 3 2 3 ::

1974
401

.._- ------

1975 :--

1976 _ --___-

__.

ALL INCIDENTS TOXIC*%
FEL'EF: ,\ ,?i,\ IT*

iA r, c ?I,! ; s ,_

315
14 4 27 83 64 2 1 4 16 18 3 3

100
73 2 3 16 12

549 113 86

. . . . . . . . . . . . .

467 89 60 3 4 1'; 2

L !!Ti!,'ifi&' : : : : Cc“~'."JLSIOtiS .
R:.Sii DYSPNEIZ : : : : : ;iYi‘ 'l: Et: SI ON CWli . . . . . . . : CYA~iGSiS . . . .

12
96 1;

2 3

14 1

: 13 14

1
2 204 235 4 04 1 s; 49

h 1
;; 60
iz

.

t
2
3 24

1

:
2

2 2

Pt:E!_iilG:lIA

...

1
23 32 50 2 54

: 20 z"3

r,I TRACT G1tlEE SIGNS': MOSPITALIZED . F;'.T::L . . . . . . . . VICTIPI .AGES
L'NDEP/\ 5YO L . . . * . 5v3 ,'$!:D OVFP L,. . .

31 43

3,878

315

398

415

401

549

467

531

; : ;

/-GE L!'jSFECiFIED VICTIW SEX !‘ \;\LE . . . . . . . . . . F'r:MLE
5::: yii&CiiIEi) 1: A 7 :: 2 Tz 0' I\ L 1,960 1,500 418 166 108 41 173 162 63 207 163 45 202 164 35 298 252 177 38

196
55

_.f- : ?'TilT /'

1:iCIDENT .I. . .

-

ROUTE, MANNER, 7.77$ 4,'. .I

INTENT, '1 r U.6.d

ETC

Ir&LlTibN' : : : S!!DSTAtICE AEUSE sI;!CII:E ClTilEE :lAilNiR' : :
U'iKtiO1d1J . . . . . . .

PERSOH CONTACTING POISON CENTER s PROFESSIOt{AL . . 1,310 2,108 LAY PERSON . . . . TYPE OF CASE TELEf'tlOllE . . . . .
T::E,:TED . . . . . . . 2,643 1,235 102 64

1::
158 157 6

'127 247

152 215 265 136 7 5

205 298 388 161

181 227 332 135 14 9

219
354 489 142

242 354 577 ;,I ^r7

197
201

237 178

OTHER CIIILDREN I!l'.,OLVED
T?EArED .::::::

. 1
:i

;

21 15

6
5

?rSE AND SUCCESS OF EMESIS, LAVAGE 1,027 . SYR OF IPECAC 7 CPf‘ PCZ SULF. :,rili’ t!?PilIfiE . 1: 520 WCCESS”UL . 40 ii:!',\!:‘ CESSI'UL . ..

81 3 52 1 64
CEtITER 110

113 1

105

85

1

102 1 66 5; 109 260 21

.

116

210 1 86

215
&9 9 41

58 7: 129 134 32 3; 34 12

L ,' ;' ;: r, r:0 . . . . . . .
SIILiSCES trcSS liC!'CC OF INFORP!ATION . . . . . . . . . C,',EDS . .-.

447
USED BY POISON 732

67 3 72 104 192 27 7 50 55 6 13 97 56 42

44 63
10

58 365

1,583
131 33 487

1:: 21
12 55 83 6

6Gb 55 109 635 367 283 123 7

41
52 8

5; 74 4

11 87 :z 15 4 70 31 11 5
OR DEATH

lG4 zz 7 76 32

15

fz
30 42 1 63 18

28 111 59 51 1 101 25

78 .I 4 ; 104 59

88 3
44

38

3 93 43
:: .

13

78 37
T 2 ‘ ; < 7:

57 30
HOSPITALIZATIOH,

= CASES

REPORTED EY PIARK I

WITit FOIi,

SIGNS PII.D.

AH!:

SYMPTOMS,

".. J I

.I.j r.i:a‘ ii?t::

(HFD2.40)

TW-ENTIETH

REV

By allthority of the United States Phar/tzacopeial Conl;cltltion, Inc., rrwetirzg at Washijrgton, L? C,, March 22, 1975. Prep~~ctl by Ihe Co~~mittee of Reoision ardpublished by the Boclrd ,fTrLtstces

,

United States Plmx~acopcial
1260 I Twinbrook Parkway, Rockvill~,

Convenfion, 1nc.
bid. ‘ 2QX.52

... . ... ....... \ i!I c’ rl.lI~II!~;. to rn‘ ll,c
:!I);. I!1 ;:txHlt Ill 14.: l(ilN

100 1’
i ()I.% II I I

SIN) 1111 lhC alwllc~l, Ol‘ ill]. t‘ iltcr, if nc’ cck

‘ cs<rx c iii tight ,

coril;iincrs,

in 3. refrig-

Y & .3 r,y C! jo Y
tlAT!ONAL CLEARINGIIOUSE FOR POISON POISOtl cot, CONTROL CENTER&FDA REPORT SUFIMARY BUREAU OF DRUGS, DIVISION OF POISON

..J
/-'AGE fin CONTROL, HFD240)

CIEGCRY 15: c.kr:Pt<oR PRODUCTS : . c, .- - ^ T 13552c: c _I, a CAPlPii3K SPIRITS - \,/ ::‘ /,.c!i CATEGORY: .- I ALL AGES ALL YEARS ~_____________________________________ 1971 1972 -----------------------25 I ; 41 9 3 1973 --------------35 11 8 1974 1975 1976 _------------------------------------------------22 6 I 5 I 29 8 3 , 2; ij 'I.8 1977 30 z 1 1 1 1 1978 14 5 3

2 2

3” 8
34 ji 22 12 7

2 : 3 :

4

:
: 2

3 3

160 29 22

13 5

31 2 2

16 ii 10 39

24 2 17 8 4

10 4 1

22 3 5 13 9 8

10 3 1

:I 8
34 34

1:

i

1

1 1

:

1

4

36
‘ pij of= CASE 7 r-L c@!!r;L{F ,.... I i?Er,rED . . . . . . .

2: 22 13

1’ :
13 9

2: 21 8

1;:
9 6

12 13 23 7

3 7 7 7

130 81

:;

20 21

.‘

a ,-

*

@

0 -._ _-_--_--._---I_ 0 ---.

1 ;. .

U S E A N D S U C C E S S F E M E S IS , L A V A G E O
S Y R O F IP E C A C . CO?PER SULF. . . :, i r""!:'PtIIN E ,I i . \ SUCCESSF U L : : : l i : : :, " r, c E s s i - IJ L . 1 /, ' VA G E D ..*,... 70

1

7 4 2

14
I 9 8

16 8 : 15 10

5 3 2 9 10 7 1 5 1

8

5 6

8

7 2

35 3 27

2 4
7 9

2
2

S O U R C E S O F IN F O R M A T IO N U S E D B Y 3 U O i :S . . . . . . . . . 78 62 N C i ' C C C ,!R D S P ? :' D !IC T L r,? E i ' : 11 y ,' ,' ;' J ' :,tC T ' i F !E R . . 1 p i ' t::.' I:,i J S i ;H !!L D G 30 25 Z i !i t;i S O !IP ,C E . . 2 !:3 T A V h IL h D L E .

P O IS O NC E N T E R
10 8 3 3

19
13 3 ;

3 r,
3 3
3 ‘I

1

z

1

4 8

p A C K :,G IN G IN F O R M A T IO N C L U S U R E IN F O S P S F E T YC A P . . . t!!l !i - S A F E T Y . . . 2: i2 i ‘i ' E t( . . . . . . . . . 20 CLGSED O R I~ !f:A L ' C O N T A ~ t~ E R O R T R A N S F E R R E D G P IG I1 IA L 21 2 l E ,:t:S F E R R i i ' : : !d /( ? t? ! !i G L A D E L 26 Y E S .., . . . . . . . 12 i :o C o !:T ~ ,i ~ ~ E R ' S i O ~ ~ G E S IT E 17 1 !S U ,:!. [' L A C E . . 4 t:o T U S U A L . . I . ~ 4 T Q u IC = C A S E S R E P O R T E D

6 t
6 1 5 1 9 8 4 O R DEAT H 5 4 4 3 3 3

2
2

1 4 1 4

2

W IT H S IG N S A N D S Y M P T O M S , H O S P IT A L IZ A T IO N ,

7-N
HATIONAL CLEAR!NGt!GUSE FOR POISON POISON CONTROL CASE REPORT SUWIARY CONTROL CENTERS (FDA BUREAU OF DRUGS, DIVISION OF POISON -: TEGORY 15: CApfPIIOR PRODUCTS L,. '>rxr\:I CT 135520: CAPiPtiOR SPIRITS .\ -c .'~r_iI?l AGE CATEGORY: UNDER 5Y0 ALL INCIDEt~TS . . TOXIC&X SIG!iS/S+r'iPi6m6 FEVER . . . . . . . ?,lAXIA 1.. . . . P!!P/:j 160 :: 34 ii 31 6’ 16 4 3 24 7 2 10 2 1

0 - .
PAGE CONTROL, FIFD2401

3

iI

i

1 1 1

1

i’ i: C;4O !I IP ::

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r?O-CilT H. Elrr~r,

Rcpion IX (Son Frcnc’ ,pco). [F‘ Dx.?5--2L’ n &s6 F’ lled G-2%76;@:45 am]
_I-.

DEf’ f\RTSEEE:T OF TRAN5PORTATION
hY:rria!s

Transportation

Dweau
ET AL

ROLF JfriSEN & ASSOCIATES, INC. Sptzial Fcimiis Issued

s 1iaxrdcu.s LTn:e:inls l?.c;u!aPurswnt to 49 CFR B 17O.IC cf the Depnrtnwnt’ tims. Is:vtd :.X~ny 23, !c’ (33 Fi1 3177). foils’ Ci; ;!.:~ is R I!st of p.cw DOT S,,etfal Uxrd!s c,xm wl:ich cct!on n‘ cccnpI&xi durhg July 1975. as ____---_-.-----.. -.----~--------~------.--.---..~-_ ..__

Cha i L-man William E. Iott~erhos, M.D. Dctors IJospital Professional 385 Medical Drive Jackson, MS 3921-6

Bldg.

Memlxrs ' Liaison Consuner Marvin LiIJnan, M.D. Consumers Union 256 Washington Street Mt. Vernon, NY: 10550 I

Chester L. Rossi, R.Ph., Torso Medical Clinic 1029 East %omas Street Pasadena, TX -77506

D.P.M.

Industry Saul A. Bell, Pharm.D. (CTFA) Che-sebrough-Ponds, Inc. 1 Research Labs. -. flrumbull, CT 066ll

I

Rose Dagirmanjian, Ph.D. Professor Pharmacology & Toxicology Dept. of Pharmacology & Toxicology Health Sciences Center University of Lr>uisville P-0. Box 35260 Wisville, KY 40201

Harry E. Morton, Sc.D. 4ll4 Sdlool Lane Drexel Hill, PA 19026

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D

Volume 160222

Subnitted

By
Center

Sub.ject Camphor

University of Nebraska Medical Carol R. Angle, M.D. University of Pennsylvania Harry E. Morton, Sc.D.

160358

Hospital

Camphw

t

;L E E T ING O F T H E P A N E L O N R E V IE W 0 : X IS C E L L A L 'E O U E X T E R N A L T C D R U GP R O D U C T S . S O
t ?( l

I 0
Panel Members

S e v e n th M e e tin g November 9 and 10, 1975 R a m a d a In n B e th e s d a , M a r y l a n d and P a r k l a w n B u ilding Rockville, Maryland Liaison R e p r e s e n ta tive s

W illiam E . L o tte r h o s , M .D., C h a i r m a n C h e s te r L . Rossi, R .P h ., D .P .M . R o s e D a g i r m a n j i a n , P h .D. ( A b s e n t) Harry E . M o r to n , S c .D. V incent J. D e r b e s , M .D. G e o r g e C . Cypress, Jr., M .D. M a r i a n n e N . O ' D o n o g h u e , M .D. FDA Members

M a r v i n M . L i p m a n , M .D. C o n s u m e r L i a i s o n (C.U.1 B r u c e S e m p le, M .D. In d u s try L i a i s o n ( P .A .) S a u l A . B e ll, P h a r m .D. In d u s try L i a i s o n ( C T F A )

R o b e r t G . P into, E s q ., Director, O T C Division T h o m a s D . DeCillis, P a n e l A d m inistrator J o s e p h Hussion, D r u g In fo r m a tio n Analyst J o h n M . Davitt, E x e c u tive S e c r e tary Invited P r e s e n ta tio n N C D C , A tla n ta

R e n a te K i m b r o u g h i - M .D.,

A lso P r e s e n t ( O p e n S e s s i o n ) W illiam Trudell ( U S V P h a r m a c e u ticals) R i c h a r d B o u r n e (Block D r u g ) M y r o n L o w e r ( R e e d & Carnrick) D a v i d O p p e n h e i m e r ( P fize r ) P h ilip D o d d ( T h e "Pink S h e e t") S ta te m e n ts m a d e h e r e i n a r e provisional in n a tu r e a n d m a y b e m o d ifie d o r revised in s u b s e q u e n t m e e tin g s o f th e P a n e l o r in th e i r fin a l c o m p l e te r e p o r t to th e C o m m issioner. W h e n e v e r th e r e is a lack o f u n a n i m i ty o n a n y g i v e n p o i n t, th e vote will R e g u l a tio n s d o n o t p e r m i t voting b y th e L i a i s o n M e m b e r s , b e given. o r F D A S ta ff M e m b e r s . Consultants, :? .-- ;,< . /t ,- i A d o p te d / ' .-. , ,' I ,'h $ ,K ,$ _ .' ~Chairman 1 ,/:;'"L '-' . / __ ,.+ c ;/: ;. ,

.

draft for

of the minutes

with

appendices prior

will

be circulated

to the Panel members

comments and corrections ingredient"s The initial

to acceptance.

The following Alcohols. for Topical

were discussed: sections of the Panel report These sections methyl, ethyl, on "Antimicrobial in general cetyl, associated review with stearyl with Drugs the and ethyl

Use" were presented. with

deal

alcohols benzyl alcohol

and specifically alcohols,

isopropyl,

and menthol.

The uses of and claims submitted to the Panel for

in the OTC products (Appendix A revised with 2).

were discussed

in some depth. Pyrethrins. were assigned

Panel

report

was presented.

The following

categories

regard Pyrethrins .

to efficacy

as .a pediculocide: 0.2% plus piperonyl butoxide

Category I. (synergist) 2%. Category III. With regard Category III,

0.3% or pyrethrins alone at lower

Pyrethrins all

than 0.3% concentration. have been placed into absorption

to safety, mainly hazards

pyrethrins

preparations

because

of the lack

of information 3)

on percutaneous

and possible

in pregnancy. of the synergists report, for

(Appendix

Judgement on safety Camphor. Acetone. Salicylic

has been deferred background on this information ingredient report

to a future only,

meeting.

A preliminary A revised Acid. draft

was presented.

of a report discussed.

was presented. is being prepared.

Briefly

A new Panel

-2-

h

SlIMMARYMINUTES OF THE OTC REVIEW PANEL ON MISCELLANEOUS EXTERNAL DRUG PRODUCTS Eleventh
May 16 and 17,

I4eeting 1976

*:'-' Panel Members

Holiday Inn Bethesda, Maryland Liaison Members

William E. Lotterhos, M.D. chairman M.D. (absent) George C. Cypress, Rose Dagirmanjian, Ph.D. Vincent J. Derbes, M.D. Harry E. Morton, Sc.D. Marianne N. O'Donoghue, M.D. Chester L. Rossi, D.P.M.

Consumer Marvin Lipman, M.D. Consumers Union Industry Bruce Semple, M.D; Proprietary Association Saul A. Bell, Pharm.D. Cosmetic, Toiletry h Frangrance Assoc.

FDA Staff

Members

. 0

Secretary John Md Davitt '; Executive Michael Kennedy - Panel Administrator Victor Linamar)c, Pharm.D. -.Drug Information

Analyst

Statements made herein are provisional in nature and may be modified or revised in subsequent meetings of the Panel or in their final complete report to the Commissioner. Whenever there is a iack of unanimity - on any given point, the vote will - Regulations do not permit voting by the Liaison Members, be given. Consultants, or FDA Staff Members.

.

Open Session No formal for open session open session discussion the Third was held, .since there had been no requests

or presentations. Conference D.C.),

On May 17, the Panel (Marriott by the American

members attended Twin Bridges Medical

on Cutaneous Toxicity jointly sponsored

Motel,

Washington,

Association Dr.

and the Society

of Toxicology. attended

This was a two-day on the second

conference;

Dagarmanjian well.

and Mr. Davitt

day (May 18)'as Closed Session Minutes Minutes Tannic Acid

of the previous (Tannins): draft

(10th)

meeting

were reviewed

and approved.

The preliminary

report

presented

at the seventh and expanded.

meeting The expanded

(November 9 and 10, 1975) has been revised draft

(Addendum A) was discussed during this session. The current Panel . positions on tannic acid preparation of several therapeutic classes are . as follows: 1. plants Treatment of contact dermatitis family: due to Rhus spp. and/or other

of the Anacardeaceae

efficacy

has not been established. (and consequently to large II.

Because of the possiblity an increased potential for

of significant systemic

absorption

toxicity)

when applied fall into

areas of the integument,

these preparations

Category

2. actually cipitate checking III).

Treatment

of minor

wounds: it

although that

clinical
tannic

efficacy acid would a protective hemorrhage

has not precoating, (Category

been established, tissue proteins

is possible

in an abraded

area<

forming

excessive This

secretion

and stopping acid for this I),

superficial indication provided

use of tannic standpoint

would

be acceptable is limited

from the safety

(Category

application

to an area of 1 sq cm or less. 3. Herpes simplex for this (labial fever blisters): but astringent tannic efficacy acid has not

been established inasmuch

indication, applied on this

may be beneficial to III).

as any topically effect

would

be expected

have a desirable 4. completely 5. Zirconium Treatment

type of herpetic toenails: efficacy

lesion

(Category

of ingrown

and safety

not yet

reviewed. Antimicrobial Compounds and zirconium carbonate . remedies. There is insufficient dermatitis, and Epstein, although a report oxide are currently evidence used claims: to be discussed at a future session.

Both zirconium in OTC poison in treatment investigators indicates ivy

of efficacy

of rhus (Maibach

from one group of 1964)

Postgrad.

Med. 35:571,

efficacy is

as a rhus dermatitis concerned about

preventive. of certain zir-

The Panel

the known potential local reactions

conium compounds for in sensitive placed into

producing

adverse these

(granulomata) been

individuals. Category II,

Hence, re: safety.

compounds have tentatively

2

Camphor A preliminary report had been presented A expanded draft at the seventh was discussed meeting and retied

(November 9 and 10, 1975). at this . session. feels that

The Panel

additional

information

on the percutaneous risk in pregnancy is

absorption

of camphor is

needed in order

to assess

(camphor crosses an important request

the placenta)

and in the newborn . Industry pertinent

(glucuronidation members will is

detoxication to provide

mechanism). whatever

liaison information

industry

available.

Denatonium

Benzoate: an interim currently (13 week) report being conducted with on the chronic by the International Denatonium by gavage, at

The Panel has received oral toxicity study in rats

Research benzoate

and Development is being of 1.6,

Corp.

under contract

HUD. rats

administered

to male and female Five rats

dose levels

8 and 16 mg/kg/day.

of each sex from at 13 weeks.

each dosage group were sacrificed Alcohols A revised microbial mation activity by the Panel. report

and necropsied

on preparations

containing

isopropanol for

for

anti-

was presented,

discussed,

and received

infor-

Pyrethrins To date, inquiry health officials of 21 states hypersensitivity. problem have responded Thus far, to the Panel's the replies .

regarding

pyrethrins an allergy

have not indicated

(Addendum B).

3

. .

Future

Meetings The next meeting of the Panel has, been rescheduled During will for Sunday (July 12) on the

and Monday, July representatives safety'

IL and 12, 1976. of Block

the open session

Drug Co, Inc.

make a presentation butoxide pediculocides.

and efficacy

of pyrethrins-piperonyl

n

l

4

TANNIN

In 1611 Cotgrave' wherewith tannin being small

defined

tan as: is

"The barke tanned".

of a young Oake,
to

beaten, term for

leather a widely

According

Reid' of

is a generic origin,

occurring raw hides

group of substances
into

vegetable tannin 50-60X,

capable acid) nutgall occurs

of rendering

leather. nutgall present

common contains in, tea, source is 2

(tannic Chinese

in oak gallnuts 702); tannins Tannin

(Turkish are also

about

sumac, oak bark, known as cutch, The usual

and mangrove bark. and is produced

from the latter scale, especially breaking

on a large

in Malaya. or crushing

method of preparation into small pieces;

involves these

the bark or gallnuts with water until

are then washed and boiled After separation of _ '

insoluble

the tannin -. . matter, the thick, tannin

has been extracted. reddish-brown,

viscous Purification

extract

is evaporated, by

0

leaving extracting deposits

the crude

as a hard cake. with

may be effected mixture; mass. evaporation Tannic oxy-

the crude material the tannic acid

an alcohol-ether

as a colorless,-noncrystalline by heating gallic acid with

acid may also chloride. 2

be prepared

phosphorus

Substances often of greatly

capable different

of tanning, chemical

and hence called all of hides into

tannins,

are

structure;

tannins, into leather. soluble

however, insoluble fn general, in water or

have the property nonputrefying tannins

of converting

the gelatin

material,

thus changing when solid,

the hide but

are noncrystalline

readily

1

age L

alcohol

to give colloidal

solutions

that

are strongly because they 2 .

astrigent.

Tannins

have long been used in compounding inks,

form greenish-black

0

or bluish-black

colors

with

ferric into

salts.

Tannins may be divided tannins clude that

three m a in classes: either by acids tannins

(1) condensed in-

cannot be hydrolyzed

or enzymes (these

the acacatechin all contain tannins,

and isoacacatechin highly for substituted example,

and the g a m b ir catechin nuclei); (2) and

tannins;

phloroglucinol

hydrolyzable caffetannins,

gallotannins,

ellagitannins, nature.

and (3) tannins

of unclassified

G a llotannin, and m e d icine, esters

from which is obtained in oak galls. It

the tannic is a m ixture

acid

of commerce acid

is present

of the gallic These esters

of glucose,. depsides. It

one of which is pentadigalloylglucose. Tannic acid, USP, is a m ixture powder of very

are called tannin styptic type.

of compounds of gallotaste, widely used in used

is a light-yellow and ointments.

astrigent

preparations practice in 1850.'

Tannic acid was formerly

in m e d ical published

as may be seen from these quotations "I

from an article in every and have

have been accustomed to use the tannin astrigent seemed to be indicated

case where a strong

and active its

never had reason to regret of dysentery, there diarrhea,

exhibition...more infantum and other to almost of

than one thousand cases bowel affections... any extent...except the last stages of for

cholera

is no danger in the use of tannin I have used it hemorrhage...in diseases

constipation... phthisis,.in

in the sweating threatened

abortfon...in

hemorrhofds...fn

aphthae and other

of the mouth . ..in

old sores and phagedenic

Page 3
. .

ulcers." By contrast one of the leading in the section textbooks dealing with of pharmacology, tannic this acid that states: A .

0
-

of Goodman and Gilman "there review are few if

any legitimate tannic its fall acid from

medical

uses for

substance".

of the use of explain

in the treatment favor

of burns

and in barium

enemas will

among physicians. the use of areas tannic with acid dry of a The enough

A half in burns. sterile tannic bath

century

ago DavidsonS

introduced

His method consisted pads which

of covering

the burned

pads were then soaked with treatment was modified

a 2.57. aqueous solution in 1936, whereby in it. but

acid. of tannic

This acid

by Wells'

was prepared of tannic to give acid it

and the patient

was immersed important

precise

percentage

was not considered

was put in the water . was followed hours 0 solution

"a good muddy appearance". to a dry bed and for constantly dried with

The tub bath about 72

by transferring areas acid

the patient

the burned of tannic

were sprayed Feediately

more or less and thoroughly describ-ed

with

a 51.

a blower. of the was

In 1941 Buis liver possible nately following in five deaths burns.

and Hartman

the histopathology tissue

At the Henry Ford Hospital of death fall following under to that clinical

examination burns. of

instances

superficial

Unfortu-

following

burns

the jurisdiction which could

the coroner at the

and tissue usually logical

examination

was limited A brief

be obtained

incomplete finds

autopsy.

summary and the histopathomerited of no official areas.

were presented. the exception

The gross of the extent

findings

comment with

and degree

the burned

li'age 4

.

Treatment, discussed

while in detail primary

adapted

to individual

by McClure shock if

needs followed the principles as 8, 9, 10 and consisted of: a) and Lam b) ade.quate sedation; d) tanning transfusions with tannic c) debridement-acid jelly;

0

combatting general

present; advocated; f)

anesthetic of

was not fluid

e) restoration blood

balance;

of blood

plasma and whole

as indicated if

by repeated indicated.

hemoglobin

or hematocrit

determinations;

g) oxygen therapy Case 1. skin hours. Liver: degree cellular areas. of lower

White

man, age 21. hands,

Steam scald

of head,

neck, Survived

entire 18

extremities,

wrists,

and forearms.

Focal

areas

of degeneration dissociation of

centrally

located,

varying to indefinite

in

from necrosis detail. Small

and complete infiltration

of the cords

Diffuse deposits

lymphocytes I

in the periportal

of bile

pigments. First

Case 2. shoulders, Survived

White man, age 45. at 25 per cent

degree burn of chest by caustic

and soda.

estimated 90 hours. Liver:

of body surface, . -

Extreme be identified

destruction as liver. retained of large

of

the parenchyma; Only a few hepatic of structure. areas,

some sections cells near the con-

could

hardly

periphery sisted for

of the lobule the most part phagocytic with cells

a semblance vacuolated

Tissue debris, areas

cellular

pigments, infiltrated The cells degenerative

and some exudate. and an occasional ducts were better was quite

The periductal

were

lymphocytes bile

polymorphonuclear preserved characteristic but also

leukocyte. showed

of the small change.

The picture

of a toxic

rage 3

*

hepatitis. Case 3. White girl, age 6. Clothing caught fire from stove. mainly the trunk acid '

0

An estimated and thighs. bath.

45 per cent Treatment

of body surface cortin

burned

involving

included

and immersion

in a tannic

Succumbed in 50 hours. Liver: Fairly uniform Slight throughout. decrease with Hepatic cords intact. No No prolff-

evidence eration

of necrosis. of ducts Case 4.

in intensity inflammatory Fell into legs a pit

of stain. cells. of steaming

or infiltration

White man, age 43.

sand up 20

to hips days.

with Icterus

second degree burns index off varied at 15-20.

of both

and thighs.

Survived

from 60 to 80 units

from the 4th

to the 8th

day and leveled Liver: from true zonal 0

Marked widespread to congestion.

degeneration Extensive of

of the parenchyma vacuolization. the cord cells.

varying

necrosis

Change not Slight

in distribution. in periportal Case 5.

Some regeneration fibrous tissue.

increase

No increase -Burned by flame,

in ducts. head, neck, hands Survived

White man, age 19.

and legs, 90 hours.

the area was estimated Icterus Liver: index Similar gradually

at 25 per cent increased Extensive

of body surface.

up to 83 on the 3rd day. necrosis near of cord cells with of the

to Case 2.

only lobule. plasm.

an occasional The nuclei

recognizable did not

cluster

of cells

the periphery

show as extensive could

fragmentation

as the cyto-

Ghost outlines cellular debris,

of sinusoids

be detected. Fairly intense

Considerable infiltration with

pigment,

and exudate.

inflammatory fibrous tissue

cells, which of cord

mostly also cells

lymphocytes. supported or ducts, of animal

Slight

increase

in the periductal No evidence of

many lymphocytes. the latter experiments being

regeneration

better

preserved. to determine

In view of this if similar

a series

was planned

changes could Normal, healthy

be produced, animals,

two phases of which

are reported

here.

u

ranging

from 12 to 15 kilograms anesthesfa

in weight the skin degree

were shaved over was exposed burns.

the back and sides. sufficient

Under adequate

to a bunsen burner time of this

to cause second and third was five minutes. areas

The average

process

Approximately was immediately

35 to 65 per cent covered treatment administered 36 hours with

of the body was burned. jelly,

The burned

resorcitannol

the same as that returned sulphate),

used in the clinical cages. Sedation was

of burns,

and the animals (morphine

to their

as indicated

in no instance to food and water.

for more than No other days and on hemoglobin, to survive and the

post burn. was given.

The an5mals had access Daily determinations

0

treatment alternate

for

the

first

five count,

days thereafter and icterus

were made of the erythrocyte index. exposing The animals . _

plasma protein, until animals the eschar

were allowed surface,

was broken,

raw granulating This period varied

showed signs The blood

of discomfort.

from 10 to 18 days. described hemoglobin, as and _ 1' ; !' .

changes were those increased erythrocyte

characteristically count, which increased

following

burns, fall

an immediate normal limits.

of plasma protein
The icterus index deaths

gradually

returned

to within limits in

did not vary in the series.

beyond normal

any case.

There were three

At autopsy A thin

there

was no evidence organizing

of infection

in

the burned in

area.

Layer of jelly-like Nothing noteworthy

serum was present

the subcutaneous of the a

0

tissue. viscera; dark

was found in the gross in appearance, On section having a lightly

examination the surface

The livers

were uniform and dry.

smooth,

reddish

brown color, surface,

some blood mottled

could

be expressed

from the cut

the latter

nutmeg appearance.

There was no suggestion Microscopically, days and in those group the positive The liver dying

of ulceration the findings within 48 hours

in the stomach and duodenum. in the animals differed living a number of In the liver first

sharply.

findings

were confined of the sinusoids

to the lungs,

and brain. empty or those near the

showed dilatation red blood cells.

which were either cells, especially

engorged with center

The liver

of the lobule,

were correspondingly degeneration.

compressed

and in various congestion

stages in

of granular the lungs, small

and vacuolar

There was moderate presented

but no consolidation. perivascular . in a few instances. dying with

The brain and pericellular

congestion

of' the

vessels

edema and degeneration

of cells

In the animals and. the kidney brain. observed In these

in 48 hours changes,

or less, as did also

all

organs the liver, with

were congested lungs those that cells by is, and

showed definite animals

the liver dying

changes were identical within

in the human cases of

a few days of the injury; necrosis of the liver

marked congestion involving hemorrhage.

the sinusoids,

extensive

from one-fourth Hemorrhagic

to three-fourths infiltration

of the lobule,

accompanied

was seen in

the lungs.

The kidneys

showed granular

and vacuolar

degeneration

or the tubules

and the brain

Page
.

a

.

pericellular cells

and perivascular

edema with cells

degeneration of the base.

of the pyramidal

of the cortex

and the ganglion

0

In 1962 Wells, who had died their attention of "toxemia"

Humphrey and Co11 following Helpern

11.

c reported

four

patients

of theirs

burns;

an additional Medical

case was drawn to Examiner of New

by Milton

then Assistant

York City. The four and their lobular death. patients who died of "toxemia" because lesion were of particular each one exhibited or as the sole interest, central cause of

cases were briefly liver necrosis

presented

as an outstanding

Treatment of these patients followed the general principles laid 6 down by Wells: the employment of a tannic acid tub in which-a careful debridement secured a tannic current was done without case; an anesthetic, a thin, sterile tan being by the use of dry by a
.

in every acid

the tan was subsequently and for the most part hair

maintained perfectly

spray,

was kept drier.

of warm air Case 1.

from a commercial old boy,

A 17 yea; his clothing

was admitted

on July

1, 1937.

Practically

all

had been burned-off from a bystander's less than five-sixths

when a can of gasoline cigarette. The bums body solution,

he was holding were estimated surface. the loose hours tannic

became ignited to involve not

of the entire acid

The patient skin

was imediately

put shaved. to bed, dried

in a tub of tannic He remained was sprayed with all in

removed and the hair being transferred and immediately On microscopic

the tub 4 l/2 with drier. the liver a

and, after acid

repeatedly hair

solution

a commercial organs

Autopsy.

examination,

except

. . showed nothing thirds but cloudy lobule, cytoplasm area. swelling and congestion. cells In the central showed a granular, normal the nuclei cells were two-

of the liver

the parenchymal in contrast this

0

deep-pink-staining in the peripheral slightly enlarged,

to, the relatively central zone,

Throughout

and there were present

were numerous necrotic in the peripheral

foci. zone.

A moderate The sinusoids . 18, 1938. An were

number of mitoses distended with Case 2. electric head, on both flash the torso thighs,

blood.

There was no leukocytic old man, was admitted room had ignited both upper

infiltration. on August his

A 23 year

in a transformer to the waistline, both anteriorly acid

clothing.

‘ The entire

extremities

and wide patches The patient

and posteriorly, solution

were burned.

was put in a tub of tannic debrided. by repeated dried gross 0 life, before with fluid He remained spraying

and carefully This

and thoroughly treatment was followed

in the tub 2 3/4 hours. a tannic hair drier. acid solution,

with

which was immediately were given, the last About 24 hours two hours pain after in and no of

a commercial imbalance

Three transfusions apparent . until

was clinically

when edema of the lower death, the patient

extremities

became restless, several

developed. _ complained He died

of severe 96 hours

the upper admission.

abdomen, and vomited

time’ s,

Autopsy.
a

The liver with

weighed

2000 gm., and the cut The gall bladder

surface

showed

fine

mottling,

hemorrhagic

points.

and biliary

ducts

were not unusual., examination, The central

No ulceration significant

of the duodenal histologic of the liver

mucosa was found. to

On microscopic the liver.

changes were limited lobules

three-fourths

showed extensive

hemorrhagic A few cells

necrosis,

with

complete region A slight

disruption were still diffuse.

of

the cords

of liver

cells. these

in the peripheral division.

intact,

and some of

were in mitotic 0 nuclear fat leukocytes

infiltration together with

of polymorphoa scattering of

was present

throughout, in

globules. Case 3.

There was no increase A 23 year

fibrous

tissue. on April 26, 1940. An

old man was admitted gas bad resulted back and both put

explosion face

of illuminating upper chest,

in burns arms except

involving for tannic

the entire the

and neck,

the palms of acid -solution,

hands.,

The patient

was immediately debridement being

in a tub of out.

where a thorough 2 l/4 acid hours. solution

was carried

He remained sprayed hair

in the tub for with drier. and flabby. The a tannic

After

removed, dried weighed

he was repeatedly with a commercial

and immediately The liver a finely bile

Autopsy. cut dark ducts surface thick

1240 gm.,

and was soft

revealed concentrated

mottled in a small

red-and-yellow thin-walled thin, clear

appearance.' gall bile. bladder.

There was The bile

were not

remarkable

and contained central

Microscopic involving of the liver areas. more cords. These nuclei, some of of

examination than three

showed extensive quarters

of the liver cells

hemorrhagic necrosis . lobule, with disruption remained

Only a narrow cells with which varied irregularly

zone of intact markedly in size

in the peripheral reaction. figures

and staining Mitotic

Many had large were present, Definite

clumped

chromatin. scattered

were bizarre

forms with

chromosomes.

evidence in slight cells. A

regeneration degree moderate tissue. through

was not demonstrated. the area of necrosis

Fat globules

were present liver

and in the remaining leukocytes infiltrated

number of polymorphonuclear

the interstitial

Page 11 \ . Case 4. While fire left fingers tannic This which the patient and the flames side of A 26 year old man, was admitted under his own car, on September a pan of bums 18, 1940. caught the

was working spread neck, hand.

gasoline involved

to his chest,

clothing.. whole

Diffuse left.upper

the face,

extremity

and the in a tub of hours. solution,

of the right acid solution

The patient

was put

immediately

and debrided.

He remained spraying

in the tub 4 l/2 with tannfc acid

treatment

was followed dried

by repeated with

was immediately Autopsy.

a commercial 2390 gm.

hair

drier. areas with were lobule of

The'liver

weighed The cut

There were multiple yellow brown,

subcapsular small not

hemorrhage.

surface

was a pale bladder almost

hemorrhagic remarkable.

-areas throughout. On microscopic

The gall

and bile

ducts 1Lver

examination

the entire foci in

was involved

in hemorrhagic cells

necrosis.

Only in small

the periportal Slight diffuse

areas were intact leukocytic

present,

and mitoses

were infrequent. in moderated little

infiltration

was present. and viable

Fat globules tissue.

amount were evidence

0

noted of bi.le

in both necrotic stasis.

There was very

In the case of Dr. Milton severely was tannic after scalded acid over the face, nitrate.

Helpem, trunk

a thirteen-month-old The local eFghty-two

boy was treatment hours

and extremities. The patf.ent died

and silver

the bum was sustained. Autopsy. The liver weighed but showed a moderate were red.

340 gm.

The organ was of normal The central the liver

shape; parts cells

it

was firm

yellow

discoloration. half

of the lobules

In the central

of the lobule

were-more liver cells

pale-staining were pyknotic, cells

than in

the peripheral

half.

The nuclei no nuclei.

of many Some of

and some cells

contained cells

0

the liver half

were eosinophilic. many fat of vacuoles

The liver

in the peripheral normal. the proved to be that tannic cases acid

contained

but were otherwise cases and particularly appeared

On review coming to necropsy, had been employed to investigate damage, a series the effect

the reported

the common denominator in the treatment. role

Because it of tannic acid

seemed to be of interest

the possible

of experiments

was planned

in the production of liver 11 to determine by Wells et al acid on the liver Tannic injections in rats. acid of a did not absorpon the Zenker's and cosin. varying over amounts

*

of subcutaneous rats U.S.P., weighing fluffy)

injections

of tannic

Albino (Mallinkrodt,

70 to 90 gm. were selected. was employed. acid Subcutaneous

5 or 10 per cent exceed 1.5 cc'at tion. third fluid,

solutibn

of tannic

were given leakage

in doses that

any one site, was used. The tissues sections were injected, tannic

to avoid Rats that

and to facilitate were killed
or

No anesthesia or fourth day.

survived
by

were fixed . with -

formalin hematoxylin

and suitable The rats

were stained usually acid in

in groups of 6, with from one to eight injected, 8 failed sites

(0.05

to 0.40

pm.) of hours.

a period

of forty-eight Every

Of the 77 rats

to survive. damage, which, injected in

one of the remainder varied directly sites except

showed some degree of liver with the amount of tannic All other cloudy acid

general,

and the presented

number of injection a normal appearance

employed. for a slight

organs swelling.

examined

Ii /!
ii

it

!I

The liver solution portion

damage produced by: a variable

by these necrosis

injections

of cells in of

tannic in

acid the central

was characterized of the lobule;

of the liver cells

zone of intact

the peripheral with

area exhibiting irregular bizarre liver

a granular

cytoplasm

and enlargement nuclear material;

the nuclei, regular and

clumping mitoses,

of hyperchromatic some with dispersion

of chromosomes,

prominent

in the

cells

at the periphery which

or the Lobule; in minor

and hemorrhage degree to the in areas fact with that

and leukocytic of necrosis. in these experi-

infiltration,

were present

Attention ments the degree tannic acid

was called of liver

particularly

damage varied

directly

the total

amount of

solution

injected. in the cases presented liver necrosis. above died largely or solely

The patients as the result observed acid only

of a central

Such a necrosis with tannic

has been acid. Tannic

when the patient

has been treated

is no longer

used in the treatment 12 published

of burned article that

patients. advocating mucosal the use of patterns tablespoonful prior that

In 1946 Hamilton. tannic acid

a brief

in barium
films acid

enemas. could

He observed be obtained

better

on the evacuation of powdered tannic to the administration this became routine this

by adding barium

one level

to each two quart

and water

mixture

of the enema.

Results

were so satisfactory at which acid of

at the Army General the addition of

Hospital tannic

he was stationed. sulfate was recommend-

Following suspensions

article

to barium the colon

in the roentgenographic

examination

ed by a number of authors13*

14* 15¶ 16.

Related Interests

iA r, c ?I,! ; s ,_

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USED BY POISON 732

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10

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SIGNS PII.D.

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SYMPTOMS,

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(HFD2.40)

TW-ENTIETH

REV

By allthority of the United States Phar/tzacopeial Conl;cltltion, Inc., rrwetirzg at Washijrgton, L? C,, March 22, 1975. Prep~~ctl by Ihe Co~~mittee of Reoision ardpublished by the Boclrd ,fTrLtstces

,

United States Plmx~acopcial
1260 I Twinbrook Parkway, Rockvill~,

Convenfion, 1nc.
bid. ‘ 2QX.52

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tlAT!ONAL CLEARINGIIOUSE FOR POISON POISOtl cot, CONTROL CENTER&FDA REPORT SUFIMARY BUREAU OF DRUGS, DIVISION OF POISON

..J
/-'AGE fin CONTROL, HFD240)

CIEGCRY 15: c.kr:Pt<oR PRODUCTS : . c, .- - ^ T 13552c: c _I, a CAPlPii3K SPIRITS - \,/ ::‘ /,.c!i CATEGORY: .- I ALL AGES ALL YEARS ~_____________________________________ 1971 1972 -----------------------25 I ; 41 9 3 1973 --------------35 11 8 1974 1975 1976 _------------------------------------------------22 6 I 5 I 29 8 3 , 2; ij 'I.8 1977 30 z 1 1 1 1 1978 14 5 3

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HATIONAL CLEAR!NGt!GUSE FOR POISON POISON CONTROL CASE REPORT SUWIARY CONTROL CENTERS (FDA BUREAU OF DRUGS, DIVISION OF POISON -: TEGORY 15: CApfPIIOR PRODUCTS L,. '>rxr\:I CT 135520: CAPiPtiOR SPIRITS .\ -c .'~r_iI?l AGE CATEGORY: UNDER 5Y0 ALL INCIDEt~TS . . TOXIC&X SIG!iS/S+r'iPi6m6 FEVER . . . . . . . ?,lAXIA 1.. . . . P!!P/:j 160 :: 34 ii 31 6’ 16 4 3 24 7 2 10 2 1

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Rcpion IX (Son Frcnc’ ,pco). [F‘ Dx.?5--2L’ n &s6 F’ lled G-2%76;@:45 am]
_I-.

DEf’ f\RTSEEE:T OF TRAN5PORTATION
hY:rria!s

Transportation

Dweau
ET AL

ROLF JfriSEN & ASSOCIATES, INC. Sptzial Fcimiis Issued

s 1iaxrdcu.s LTn:e:inls l?.c;u!aPurswnt to 49 CFR B 17O.IC cf the Depnrtnwnt’ tims. Is:vtd :.X~ny 23, !c’ (33 Fi1 3177). foils’ Ci; ;!.:~ is R I!st of p.cw DOT S,,etfal Uxrd!s c,xm wl:ich cct!on n‘ cccnpI&xi durhg July 1975. as ____---_-.-----.. -.----~--------~------.--.---..~-_ ..__

Cha i L-man William E. Iott~erhos, M.D. Dctors IJospital Professional 385 Medical Drive Jackson, MS 3921-6

Bldg.

Memlxrs ' Liaison Consuner Marvin LiIJnan, M.D. Consumers Union 256 Washington Street Mt. Vernon, NY: 10550 I

Chester L. Rossi, R.Ph., Torso Medical Clinic 1029 East %omas Street Pasadena, TX -77506

D.P.M.

Industry Saul A. Bell, Pharm.D. (CTFA) Che-sebrough-Ponds, Inc. 1 Research Labs. -. flrumbull, CT 066ll

I

Rose Dagirmanjian, Ph.D. Professor Pharmacology & Toxicology Dept. of Pharmacology & Toxicology Health Sciences Center University of Lr>uisville P-0. Box 35260 Wisville, KY 40201

Harry E. Morton, Sc.D. 4ll4 Sdlool Lane Drexel Hill, PA 19026

Marianne N. O'Donoghue, M.D. Qakbrook Professional Building Oakbrook, IL 60521

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J. Robert Hewson, M.D. 3301 Harden Street Columbia, SC 29203

D

Volume 160222

Subnitted

By
Center

Sub.ject Camphor

University of Nebraska Medical Carol R. Angle, M.D. University of Pennsylvania Harry E. Morton, Sc.D.

160358

Hospital

Camphw

t

;L E E T ING O F T H E P A N E L O N R E V IE W 0 : X IS C E L L A L 'E O U E X T E R N A L T C D R U GP R O D U C T S . S O
t ?( l

I 0
Panel Members

S e v e n th M e e tin g November 9 and 10, 1975 R a m a d a In n B e th e s d a , M a r y l a n d and P a r k l a w n B u ilding Rockville, Maryland Liaison R e p r e s e n ta tive s

W illiam E . L o tte r h o s , M .D., C h a i r m a n C h e s te r L . Rossi, R .P h ., D .P .M . R o s e D a g i r m a n j i a n , P h .D. ( A b s e n t) Harry E . M o r to n , S c .D. V incent J. D e r b e s , M .D. G e o r g e C . Cypress, Jr., M .D. M a r i a n n e N . O ' D o n o g h u e , M .D. FDA Members

M a r v i n M . L i p m a n , M .D. C o n s u m e r L i a i s o n (C.U.1 B r u c e S e m p le, M .D. In d u s try L i a i s o n ( P .A .) S a u l A . B e ll, P h a r m .D. In d u s try L i a i s o n ( C T F A )

R o b e r t G . P into, E s q ., Director, O T C Division T h o m a s D . DeCillis, P a n e l A d m inistrator J o s e p h Hussion, D r u g In fo r m a tio n Analyst J o h n M . Davitt, E x e c u tive S e c r e tary Invited P r e s e n ta tio n N C D C , A tla n ta

R e n a te K i m b r o u g h i - M .D.,

A lso P r e s e n t ( O p e n S e s s i o n ) W illiam Trudell ( U S V P h a r m a c e u ticals) R i c h a r d B o u r n e (Block D r u g ) M y r o n L o w e r ( R e e d & Carnrick) D a v i d O p p e n h e i m e r ( P fize r ) P h ilip D o d d ( T h e "Pink S h e e t") S ta te m e n ts m a d e h e r e i n a r e provisional in n a tu r e a n d m a y b e m o d ifie d o r revised in s u b s e q u e n t m e e tin g s o f th e P a n e l o r in th e i r fin a l c o m p l e te r e p o r t to th e C o m m issioner. W h e n e v e r th e r e is a lack o f u n a n i m i ty o n a n y g i v e n p o i n t, th e vote will R e g u l a tio n s d o n o t p e r m i t voting b y th e L i a i s o n M e m b e r s , b e given. o r F D A S ta ff M e m b e r s . Consultants, :? .-- ;,< . /t ,- i A d o p te d / ' .-. , ,' I ,'h $ ,K ,$ _ .' ~Chairman 1 ,/:;'"L '-' . / __ ,.+ c ;/: ;. ,

.

draft for

of the minutes

with

appendices prior

will

be circulated

to the Panel members

comments and corrections ingredient"s The initial

to acceptance.

The following Alcohols. for Topical

were discussed: sections of the Panel report These sections methyl, ethyl, on "Antimicrobial in general cetyl, associated review with stearyl with Drugs the and ethyl

Use" were presented. with

deal

alcohols benzyl alcohol

and specifically alcohols,

isopropyl,

and menthol.

The uses of and claims submitted to the Panel for

in the OTC products (Appendix A revised with 2).

were discussed

in some depth. Pyrethrins. were assigned

Panel

report

was presented.

The following

categories

regard Pyrethrins .

to efficacy

as .a pediculocide: 0.2% plus piperonyl butoxide

Category I. (synergist) 2%. Category III. With regard Category III,

0.3% or pyrethrins alone at lower

Pyrethrins all

than 0.3% concentration. have been placed into absorption

to safety, mainly hazards

pyrethrins

preparations

because

of the lack

of information 3)

on percutaneous

and possible

in pregnancy. of the synergists report, for

(Appendix

Judgement on safety Camphor. Acetone. Salicylic

has been deferred background on this information ingredient report

to a future only,

meeting.

A preliminary A revised Acid. draft

was presented.

of a report discussed.

was presented. is being prepared.

Briefly

A new Panel

-2-

h

SlIMMARYMINUTES OF THE OTC REVIEW PANEL ON MISCELLANEOUS EXTERNAL DRUG PRODUCTS Eleventh
May 16 and 17,

I4eeting 1976

*:'-' Panel Members

Holiday Inn Bethesda, Maryland Liaison Members

William E. Lotterhos, M.D. chairman M.D. (absent) George C. Cypress, Rose Dagirmanjian, Ph.D. Vincent J. Derbes, M.D. Harry E. Morton, Sc.D. Marianne N. O'Donoghue, M.D. Chester L. Rossi, D.P.M.

Consumer Marvin Lipman, M.D. Consumers Union Industry Bruce Semple, M.D; Proprietary Association Saul A. Bell, Pharm.D. Cosmetic, Toiletry h Frangrance Assoc.

FDA Staff

Members

. 0

Secretary John Md Davitt '; Executive Michael Kennedy - Panel Administrator Victor Linamar)c, Pharm.D. -.Drug Information

Analyst

Statements made herein are provisional in nature and may be modified or revised in subsequent meetings of the Panel or in their final complete report to the Commissioner. Whenever there is a iack of unanimity - on any given point, the vote will - Regulations do not permit voting by the Liaison Members, be given. Consultants, or FDA Staff Members.

.

Open Session No formal for open session open session discussion the Third was held, .since there had been no requests

or presentations. Conference D.C.),

On May 17, the Panel (Marriott by the American

members attended Twin Bridges Medical

on Cutaneous Toxicity jointly sponsored

Motel,

Washington,

Association Dr.

and the Society

of Toxicology. attended

This was a two-day on the second

conference;

Dagarmanjian well.

and Mr. Davitt

day (May 18)'as Closed Session Minutes Minutes Tannic Acid

of the previous (Tannins): draft

(10th)

meeting

were reviewed

and approved.

The preliminary

report

presented

at the seventh and expanded.

meeting The expanded

(November 9 and 10, 1975) has been revised draft

(Addendum A) was discussed during this session. The current Panel . positions on tannic acid preparation of several therapeutic classes are . as follows: 1. plants Treatment of contact dermatitis family: due to Rhus spp. and/or other

of the Anacardeaceae

efficacy

has not been established. (and consequently to large II.

Because of the possiblity an increased potential for

of significant systemic

absorption

toxicity)

when applied fall into

areas of the integument,

these preparations

Category

2. actually cipitate checking III).

Treatment

of minor

wounds: it

although that

clinical
tannic

efficacy acid would a protective hemorrhage

has not precoating, (Category

been established, tissue proteins

is possible

in an abraded

area<

forming

excessive This

secretion

and stopping acid for this I),

superficial indication provided

use of tannic standpoint

would

be acceptable is limited

from the safety

(Category

application

to an area of 1 sq cm or less. 3. Herpes simplex for this (labial fever blisters): but astringent tannic efficacy acid has not

been established inasmuch

indication, applied on this

may be beneficial to III).

as any topically effect

would

be expected

have a desirable 4. completely 5. Zirconium Treatment

type of herpetic toenails: efficacy

lesion

(Category

of ingrown

and safety

not yet

reviewed. Antimicrobial Compounds and zirconium carbonate . remedies. There is insufficient dermatitis, and Epstein, although a report oxide are currently evidence used claims: to be discussed at a future session.

Both zirconium in OTC poison in treatment investigators indicates ivy

of efficacy

of rhus (Maibach

from one group of 1964)

Postgrad.

Med. 35:571,

efficacy is

as a rhus dermatitis concerned about

preventive. of certain zir-

The Panel

the known potential local reactions

conium compounds for in sensitive placed into

producing

adverse these

(granulomata) been

individuals. Category II,

Hence, re: safety.

compounds have tentatively

2

Camphor A preliminary report had been presented A expanded draft at the seventh was discussed meeting and retied

(November 9 and 10, 1975). at this . session. feels that

The Panel

additional

information

on the percutaneous risk in pregnancy is

absorption

of camphor is

needed in order

to assess

(camphor crosses an important request

the placenta)

and in the newborn . Industry pertinent

(glucuronidation members will is

detoxication to provide

mechanism). whatever

liaison information

industry

available.

Denatonium

Benzoate: an interim currently (13 week) report being conducted with on the chronic by the International Denatonium by gavage, at

The Panel has received oral toxicity study in rats

Research benzoate

and Development is being of 1.6,

Corp.

under contract

HUD. rats

administered

to male and female Five rats

dose levels

8 and 16 mg/kg/day.

of each sex from at 13 weeks.

each dosage group were sacrificed Alcohols A revised microbial mation activity by the Panel. report

and necropsied

on preparations

containing

isopropanol for

for

anti-

was presented,

discussed,

and received

infor-

Pyrethrins To date, inquiry health officials of 21 states hypersensitivity. problem have responded Thus far, to the Panel's the replies .

regarding

pyrethrins an allergy

have not indicated

(Addendum B).

3

. .

Future

Meetings The next meeting of the Panel has, been rescheduled During will for Sunday (July 12) on the

and Monday, July representatives safety'

IL and 12, 1976. of Block

the open session

Drug Co, Inc.

make a presentation butoxide pediculocides.

and efficacy

of pyrethrins-piperonyl

n

l

4

TANNIN

In 1611 Cotgrave' wherewith tannin being small

defined

tan as: is

"The barke tanned".

of a young Oake,
to

beaten, term for

leather a widely

According

Reid' of

is a generic origin,

occurring raw hides

group of substances
into

vegetable tannin 50-60X,

capable acid) nutgall occurs

of rendering

leather. nutgall present

common contains in, tea, source is 2

(tannic Chinese

in oak gallnuts 702); tannins Tannin

(Turkish are also

about

sumac, oak bark, known as cutch, The usual

and mangrove bark. and is produced

from the latter scale, especially breaking

on a large

in Malaya. or crushing

method of preparation into small pieces;

involves these

the bark or gallnuts with water until

are then washed and boiled After separation of _ '

insoluble

the tannin -. . matter, the thick, tannin

has been extracted. reddish-brown,

viscous Purification

extract

is evaporated, by

0

leaving extracting deposits

the crude

as a hard cake. with

may be effected mixture; mass. evaporation Tannic oxy-

the crude material the tannic acid

an alcohol-ether

as a colorless,-noncrystalline by heating gallic acid with

acid may also chloride. 2

be prepared

phosphorus

Substances often of greatly

capable different

of tanning, chemical

and hence called all of hides into

tannins,

are

structure;

tannins, into leather. soluble

however, insoluble fn general, in water or

have the property nonputrefying tannins

of converting

the gelatin

material,

thus changing when solid,

the hide but

are noncrystalline

readily

1

age L

alcohol

to give colloidal

solutions

that

are strongly because they 2 .

astrigent.

Tannins

have long been used in compounding inks,

form greenish-black

0

or bluish-black

colors

with

ferric into

salts.

Tannins may be divided tannins clude that

three m a in classes: either by acids tannins

(1) condensed in-

cannot be hydrolyzed

or enzymes (these

the acacatechin all contain tannins,

and isoacacatechin highly for substituted example,

and the g a m b ir catechin nuclei); (2) and

tannins;

phloroglucinol

hydrolyzable caffetannins,

gallotannins,

ellagitannins, nature.

and (3) tannins

of unclassified

G a llotannin, and m e d icine, esters

from which is obtained in oak galls. It

the tannic is a m ixture

acid

of commerce acid

is present

of the gallic These esters

of glucose,. depsides. It

one of which is pentadigalloylglucose. Tannic acid, USP, is a m ixture powder of very

are called tannin styptic type.

of compounds of gallotaste, widely used in used

is a light-yellow and ointments.

astrigent

preparations practice in 1850.'

Tannic acid was formerly

in m e d ical published

as may be seen from these quotations "I

from an article in every and have

have been accustomed to use the tannin astrigent seemed to be indicated

case where a strong

and active its

never had reason to regret of dysentery, there diarrhea,

exhibition...more infantum and other to almost of

than one thousand cases bowel affections... any extent...except the last stages of for

cholera

is no danger in the use of tannin I have used it hemorrhage...in diseases

constipation... phthisis,.in

in the sweating threatened

abortfon...in

hemorrhofds...fn

aphthae and other

of the mouth . ..in

old sores and phagedenic

Page 3
. .

ulcers." By contrast one of the leading in the section textbooks dealing with of pharmacology, tannic this acid that states: A .

0
-

of Goodman and Gilman "there review are few if

any legitimate tannic its fall acid from

medical

uses for

substance".

of the use of explain

in the treatment favor

of burns

and in barium

enemas will

among physicians. the use of areas tannic with acid dry of a The enough

A half in burns. sterile tannic bath

century

ago DavidsonS

introduced

His method consisted pads which

of covering

the burned

pads were then soaked with treatment was modified

a 2.57. aqueous solution in 1936, whereby in it. but

acid. of tannic

This acid

by Wells'

was prepared of tannic to give acid it

and the patient

was immersed important

precise

percentage

was not considered

was put in the water . was followed hours 0 solution

"a good muddy appearance". to a dry bed and for constantly dried with

The tub bath about 72

by transferring areas acid

the patient

the burned of tannic

were sprayed Feediately

more or less and thoroughly describ-ed

with

a 51.

a blower. of the was

In 1941 Buis liver possible nately following in five deaths burns.

and Hartman

the histopathology tissue

At the Henry Ford Hospital of death fall following under to that clinical

examination burns. of

instances

superficial

Unfortu-

following

burns

the jurisdiction which could

the coroner at the

and tissue usually logical

examination

was limited A brief

be obtained

incomplete finds

autopsy.

summary and the histopathomerited of no official areas.

were presented. the exception

The gross of the extent

findings

comment with

and degree

the burned

li'age 4

.

Treatment, discussed

while in detail primary

adapted

to individual

by McClure shock if

needs followed the principles as 8, 9, 10 and consisted of: a) and Lam b) ade.quate sedation; d) tanning transfusions with tannic c) debridement-acid jelly;

0

combatting general

present; advocated; f)

anesthetic of

was not fluid

e) restoration blood

balance;

of blood

plasma and whole

as indicated if

by repeated indicated.

hemoglobin

or hematocrit

determinations;

g) oxygen therapy Case 1. skin hours. Liver: degree cellular areas. of lower

White

man, age 21. hands,

Steam scald

of head,

neck, Survived

entire 18

extremities,

wrists,

and forearms.

Focal

areas

of degeneration dissociation of

centrally

located,

varying to indefinite

in

from necrosis detail. Small

and complete infiltration

of the cords

Diffuse deposits

lymphocytes I

in the periportal

of bile

pigments. First

Case 2. shoulders, Survived

White man, age 45. at 25 per cent

degree burn of chest by caustic

and soda.

estimated 90 hours. Liver:

of body surface, . -

Extreme be identified

destruction as liver. retained of large

of

the parenchyma; Only a few hepatic of structure. areas,

some sections cells near the con-

could

hardly

periphery sisted for

of the lobule the most part phagocytic with cells

a semblance vacuolated

Tissue debris, areas

cellular

pigments, infiltrated The cells degenerative

and some exudate. and an occasional ducts were better was quite

The periductal

were

lymphocytes bile

polymorphonuclear preserved characteristic but also

leukocyte. showed

of the small change.

The picture

of a toxic

rage 3

*

hepatitis. Case 3. White girl, age 6. Clothing caught fire from stove. mainly the trunk acid '

0

An estimated and thighs. bath.

45 per cent Treatment

of body surface cortin

burned

involving

included

and immersion

in a tannic

Succumbed in 50 hours. Liver: Fairly uniform Slight throughout. decrease with Hepatic cords intact. No No prolff-

evidence eration

of necrosis. of ducts Case 4.

in intensity inflammatory Fell into legs a pit

of stain. cells. of steaming

or infiltration

White man, age 43.

sand up 20

to hips days.

with Icterus

second degree burns index off varied at 15-20.

of both

and thighs.

Survived

from 60 to 80 units

from the 4th

to the 8th

day and leveled Liver: from true zonal 0

Marked widespread to congestion.

degeneration Extensive of

of the parenchyma vacuolization. the cord cells.

varying

necrosis

Change not Slight

in distribution. in periportal Case 5.

Some regeneration fibrous tissue.

increase

No increase -Burned by flame,

in ducts. head, neck, hands Survived

White man, age 19.

and legs, 90 hours.

the area was estimated Icterus Liver: index Similar gradually

at 25 per cent increased Extensive

of body surface.

up to 83 on the 3rd day. necrosis near of cord cells with of the

to Case 2.

only lobule. plasm.

an occasional The nuclei

recognizable did not

cluster

of cells

the periphery

show as extensive could

fragmentation

as the cyto-

Ghost outlines cellular debris,

of sinusoids

be detected. Fairly intense

Considerable infiltration with

pigment,

and exudate.

inflammatory fibrous tissue

cells, which of cord

mostly also cells

lymphocytes. supported or ducts, of animal

Slight

increase

in the periductal No evidence of

many lymphocytes. the latter experiments being

regeneration

better

preserved. to determine

In view of this if similar

a series

was planned

changes could Normal, healthy

be produced, animals,

two phases of which

are reported

here.

u

ranging

from 12 to 15 kilograms anesthesfa

in weight the skin degree

were shaved over was exposed burns.

the back and sides. sufficient

Under adequate

to a bunsen burner time of this

to cause second and third was five minutes. areas

The average

process

Approximately was immediately

35 to 65 per cent covered treatment administered 36 hours with

of the body was burned. jelly,

The burned

resorcitannol

the same as that returned sulphate),

used in the clinical cages. Sedation was

of burns,

and the animals (morphine

to their

as indicated

in no instance to food and water.

for more than No other days and on hemoglobin, to survive and the

post burn. was given.

The an5mals had access Daily determinations

0

treatment alternate

for

the

first

five count,

days thereafter and icterus

were made of the erythrocyte index. exposing The animals . _

plasma protein, until animals the eschar

were allowed surface,

was broken,

raw granulating This period varied

showed signs The blood

of discomfort.

from 10 to 18 days. described hemoglobin, as and _ 1' ; !' .

changes were those increased erythrocyte

characteristically count, which increased

following

burns, fall

an immediate normal limits.

of plasma protein
The icterus index deaths

gradually

returned

to within limits in

did not vary in the series.

beyond normal

any case.

There were three

At autopsy A thin

there

was no evidence organizing

of infection

in

the burned in

area.

Layer of jelly-like Nothing noteworthy

serum was present

the subcutaneous of the a

0

tissue. viscera; dark

was found in the gross in appearance, On section having a lightly

examination the surface

The livers

were uniform and dry.

smooth,

reddish

brown color, surface,

some blood mottled

could

be expressed

from the cut

the latter

nutmeg appearance.

There was no suggestion Microscopically, days and in those group the positive The liver dying

of ulceration the findings within 48 hours

in the stomach and duodenum. in the animals differed living a number of In the liver first

sharply.

findings

were confined of the sinusoids

to the lungs,

and brain. empty or those near the

showed dilatation red blood cells.

which were either cells, especially

engorged with center

The liver

of the lobule,

were correspondingly degeneration.

compressed

and in various congestion

stages in

of granular the lungs, small

and vacuolar

There was moderate presented

but no consolidation. perivascular . in a few instances. dying with

The brain and pericellular

congestion

of' the

vessels

edema and degeneration

of cells

In the animals and. the kidney brain. observed In these

in 48 hours changes,

or less, as did also

all

organs the liver, with

were congested lungs those that cells by is, and

showed definite animals

the liver dying

changes were identical within

in the human cases of

a few days of the injury; necrosis of the liver

marked congestion involving hemorrhage.

the sinusoids,

extensive

from one-fourth Hemorrhagic

to three-fourths infiltration

of the lobule,

accompanied

was seen in

the lungs.

The kidneys

showed granular

and vacuolar

degeneration

or the tubules

and the brain

Page
.

a

.

pericellular cells

and perivascular

edema with cells

degeneration of the base.

of the pyramidal

of the cortex

and the ganglion

0

In 1962 Wells, who had died their attention of "toxemia"

Humphrey and Co11 following Helpern

11.

c reported

four

patients

of theirs

burns;

an additional Medical

case was drawn to Examiner of New

by Milton

then Assistant

York City. The four and their lobular death. patients who died of "toxemia" because lesion were of particular each one exhibited or as the sole interest, central cause of

cases were briefly liver necrosis

presented

as an outstanding

Treatment of these patients followed the general principles laid 6 down by Wells: the employment of a tannic acid tub in which-a careful debridement secured a tannic current was done without case; an anesthetic, a thin, sterile tan being by the use of dry by a
.

in every acid

the tan was subsequently and for the most part hair

maintained perfectly

spray,

was kept drier.

of warm air Case 1.

from a commercial old boy,

A 17 yea; his clothing

was admitted

on July

1, 1937.

Practically

all

had been burned-off from a bystander's less than five-sixths

when a can of gasoline cigarette. The bums body solution,

he was holding were estimated surface. the loose hours tannic

became ignited to involve not

of the entire acid

The patient skin

was imediately

put shaved. to bed, dried

in a tub of tannic He remained was sprayed with all in

removed and the hair being transferred and immediately On microscopic

the tub 4 l/2 with drier. the liver a

and, after acid

repeatedly hair

solution

a commercial organs

Autopsy.

examination,

except

. . showed nothing thirds but cloudy lobule, cytoplasm area. swelling and congestion. cells In the central showed a granular, normal the nuclei cells were two-

of the liver

the parenchymal in contrast this

0

deep-pink-staining in the peripheral slightly enlarged,

to, the relatively central zone,

Throughout

and there were present

were numerous necrotic in the peripheral

foci. zone.

A moderate The sinusoids . 18, 1938. An were

number of mitoses distended with Case 2. electric head, on both flash the torso thighs,

blood.

There was no leukocytic old man, was admitted room had ignited both upper

infiltration. on August his

A 23 year

in a transformer to the waistline, both anteriorly acid

clothing.

‘ The entire

extremities

and wide patches The patient

and posteriorly, solution

were burned.

was put in a tub of tannic debrided. by repeated dried gross 0 life, before with fluid He remained spraying

and carefully This

and thoroughly treatment was followed

in the tub 2 3/4 hours. a tannic hair drier. acid solution,

with

which was immediately were given, the last About 24 hours two hours pain after in and no of

a commercial imbalance

Three transfusions apparent . until

was clinically

when edema of the lower death, the patient

extremities

became restless, several

developed. _ complained He died

of severe 96 hours

the upper admission.

abdomen, and vomited

time’ s,

Autopsy.
a

The liver with

weighed

2000 gm., and the cut The gall bladder

surface

showed

fine

mottling,

hemorrhagic

points.

and biliary

ducts

were not unusual., examination, The central

No ulceration significant

of the duodenal histologic of the liver

mucosa was found. to

On microscopic the liver.

changes were limited lobules

three-fourths

showed extensive

hemorrhagic A few cells

necrosis,

with

complete region A slight

disruption were still diffuse.

of

the cords

of liver

cells. these

in the peripheral division.

intact,

and some of

were in mitotic 0 nuclear fat leukocytes

infiltration together with

of polymorphoa scattering of

was present

throughout, in

globules. Case 3.

There was no increase A 23 year

fibrous

tissue. on April 26, 1940. An

old man was admitted gas bad resulted back and both put

explosion face

of illuminating upper chest,

in burns arms except

involving for tannic

the entire the

and neck,

the palms of acid -solution,

hands.,

The patient

was immediately debridement being

in a tub of out.

where a thorough 2 l/4 acid hours. solution

was carried

He remained sprayed hair

in the tub for with drier. and flabby. The a tannic

After

removed, dried weighed

he was repeatedly with a commercial

and immediately The liver a finely bile

Autopsy. cut dark ducts surface thick

1240 gm.,

and was soft

revealed concentrated

mottled in a small

red-and-yellow thin-walled thin, clear

appearance.' gall bile. bladder.

There was The bile

were not

remarkable

and contained central

Microscopic involving of the liver areas. more cords. These nuclei, some of of

examination than three

showed extensive quarters

of the liver cells

hemorrhagic necrosis . lobule, with disruption remained

Only a narrow cells with which varied irregularly

zone of intact markedly in size

in the peripheral reaction. figures

and staining Mitotic

Many had large were present, Definite

clumped

chromatin. scattered

were bizarre

forms with

chromosomes.

evidence in slight cells. A

regeneration degree moderate tissue. through

was not demonstrated. the area of necrosis

Fat globules

were present liver

and in the remaining leukocytes infiltrated

number of polymorphonuclear

the interstitial

Page 11 \ . Case 4. While fire left fingers tannic This which the patient and the flames side of A 26 year old man, was admitted under his own car, on September a pan of bums 18, 1940. caught the

was working spread neck, hand.

gasoline involved

to his chest,

clothing.. whole

Diffuse left.upper

the face,

extremity

and the in a tub of hours. solution,

of the right acid solution

The patient

was put

immediately

and debrided.

He remained spraying

in the tub 4 l/2 with tannfc acid

treatment

was followed dried

by repeated with

was immediately Autopsy.

a commercial 2390 gm.

hair

drier. areas with were lobule of

The'liver

weighed The cut

There were multiple yellow brown,

subcapsular small not

hemorrhage.

surface

was a pale bladder almost

hemorrhagic remarkable.

-areas throughout. On microscopic

The gall

and bile

ducts 1Lver

examination

the entire foci in

was involved

in hemorrhagic cells

necrosis.

Only in small

the periportal Slight diffuse

areas were intact leukocytic

present,

and mitoses

were infrequent. in moderated little

infiltration

was present. and viable

Fat globules tissue.

amount were evidence

0

noted of bi.le

in both necrotic stasis.

There was very

In the case of Dr. Milton severely was tannic after scalded acid over the face, nitrate.

Helpem, trunk

a thirteen-month-old The local eFghty-two

boy was treatment hours

and extremities. The patf.ent died

and silver

the bum was sustained. Autopsy. The liver weighed but showed a moderate were red.

340 gm.

The organ was of normal The central the liver

shape; parts cells

it

was firm

yellow

discoloration. half

of the lobules

In the central

of the lobule

were-more liver cells

pale-staining were pyknotic, cells

than in

the peripheral

half.

The nuclei no nuclei.

of many Some of

and some cells

contained cells

0

the liver half

were eosinophilic. many fat of vacuoles

The liver

in the peripheral normal. the proved to be that tannic cases acid

contained

but were otherwise cases and particularly appeared

On review coming to necropsy, had been employed to investigate damage, a series the effect

the reported

the common denominator in the treatment. role

Because it of tannic acid

seemed to be of interest

the possible

of experiments

was planned

in the production of liver 11 to determine by Wells et al acid on the liver Tannic injections in rats. acid of a did not absorpon the Zenker's and cosin. varying over amounts

*

of subcutaneous rats U.S.P., weighing fluffy)

injections

of tannic

Albino (Mallinkrodt,

70 to 90 gm. were selected. was employed. acid Subcutaneous

5 or 10 per cent exceed 1.5 cc'at tion. third fluid,

solutibn

of tannic

were given leakage

in doses that

any one site, was used. The tissues sections were injected, tannic

to avoid Rats that

and to facilitate were killed
or

No anesthesia or fourth day.

survived
by

were fixed . with -

formalin hematoxylin

and suitable The rats

were stained usually acid in

in groups of 6, with from one to eight injected, 8 failed sites

(0.05

to 0.40

pm.) of hours.

a period

of forty-eight Every

Of the 77 rats

to survive. damage, which, injected in

one of the remainder varied directly sites except

showed some degree of liver with the amount of tannic All other cloudy acid

general,

and the presented

number of injection a normal appearance

employed. for a slight

organs swelling.

examined

Ii /!
ii

it

!I

The liver solution portion

damage produced by: a variable

by these necrosis

injections

of cells in of

tannic in

acid the central

was characterized of the lobule;

of the liver cells

zone of intact

the peripheral with

area exhibiting irregular bizarre liver

a granular

cytoplasm

and enlargement nuclear material;

the nuclei, regular and

clumping mitoses,

of hyperchromatic some with dispersion

of chromosomes,

prominent

in the

cells

at the periphery which

or the Lobule; in minor

and hemorrhage degree to the in areas fact with that

and leukocytic of necrosis. in these experi-

infiltration,

were present

Attention ments the degree tannic acid

was called of liver

particularly

damage varied

directly

the total

amount of

solution

injected. in the cases presented liver necrosis. above died largely or solely

The patients as the result observed acid only

of a central

Such a necrosis with tannic

has been acid. Tannic

when the patient

has been treated

is no longer

used in the treatment 12 published

of burned article that

patients. advocating mucosal the use of patterns tablespoonful prior that

In 1946 Hamilton. tannic acid

a brief

in barium
films acid

enemas. could

He observed be obtained

better

on the evacuation of powdered tannic to the administration this became routine this

by adding barium

one level

to each two quart

and water

mixture

of the enema.

Results

were so satisfactory at which acid of

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