Fffiort of &e safetyassessment

of Alcohol D... UntJ Toxicol.2008... htp://www.ncbi.nknnih.gov/pubnred/ I 8569I 6t

PubMed
U.S. l.lational Library of liledicine
tlational hstitutes of Flealth

DisplaySettirgs: Abstract

Int J Toicol. 2Q08;27

Suppl1:1-43.

Final report of the safetyassessment

of Alcohol Denat.,including
SD Alcohol 3-A, SD Alcohol 30, SD Alcohol 39, SD Alcohol 39-8,
SD Alcohol 39-C, SD Alcohol40, SD Alcohol 40-B,and SD
Alcohol 40-C,and the denaturants,Quassirl,Brucine
Sulfate/Brucine,and Denatonium Benzoate.
Cosnptic lrEredbnt ReviewErcert Panel.
CosrneticlngredientReview,WashirgrtonDC 20036, USA.

Abstract
AlcoholDenat.is the genericterm rced by the cosnetics industryto describedenaturedalcohol.AlcoholDenat.and
rariousspeciallydenatured(SD) alcotrolsare usedas cosrneticingredientsin a wide varietyof products.Many
denaturantshavebeenpreviouslyconsidered,on an individualbasis,as copmeticingredientsby the Cosmeticlngredient
Review(ClR) E pert Panel,whereasothers,includingBrucineand BrucineSuffate,Denatonium Berzoate,ard Quassin,
havenot previouslybeenewluated. Quassinis a bitter alkaloidobtainedfrom the wood of Quassiaamara.Quassinhas
been tsed as an irsect antifeedantard irseclicide and severalstudies denpnstrate its effectireness.At oral doses up to
1000ng/kg usirErats, Quassinwas not toxic in acuteand short-termtests, br.rtsome reversiblepiloerection,decreasein
motoractivity,ard a partialloss of rightingreflexwere foundin miceat 500 mglkg.At 1000mg/kggivenintraperitoneally
(i.p.),all micediedwithin24 h of receivingtreatrnent.In a cytotoxicitytest with brineshrimp,1 mg/mlof Quassindid not
possessany cytotoxicor antiplasmodial actiWy.Quassinadministeredto rat Leydigcells in vitro at concentrations of $25
rg/ml inhibitedboththe basaland luteinizirghormone(LH)-stimulated testosteronesecretionin a dose-relatedfashion,
Quassinat dosesup to 2.0 g/kg in drinkirgwater usingrats producedno significanteffect on the bodyweights,brnthe
rneanweightsof the testes,seminalvesicles,and epididymides were significantlyredrced, andthe weightsof the anterior
pituitaryglandswere srgnificantly increased.The spermcountsand lerels of LH,follicb-stimulatirghormone(FSl-l),and
testosteronewere significarflylower in grorps treatedwith Quassin.Brucineis a derivatirre of 2-frydrorystrychnine.
Swiss-
Webstermicegiwn Brucinebase,30 ml/kg,had an acuteoral LD(50)of '150mg/kg,with centralner\oussystem
depressionfollowedby convulsions and seizuresin some cases.In thoseanimalsthat died, respiratoryarrestwas tl€
cause.The acutei.p. LD(50)for 15 mUkgof Brucinebasewas 62.0 mg/kg,with centralr€rvoussystemdepressionprior
to the onsetof epnvulsiors, jmt as with oral Brucine.Tte acuteintra\€nous(i.v.) LD(50)was 12.0mg/kg.Brucirrewas
nonmutagenic in an AnEs assayat levelsup to 6666 mu g/plate,with ard wilhoutmetabolicactivation.ln a repeat-irsult
paich test, for a hair care prodrc{ containing47oloSD Alcohol40 (95%), h was reported that BnrcineSulfate may be
considereda nonprirnaryirritantard a norprimarysensitizer.Threedifferentsunscreenprodr.rcts (35% SD Alcohol40-8,
72.4o/o SD Alcohol40, ard 74.5o/o SD Alcohol40) did mt show any sigrs of photoalbrgyin humansubjects.Also, these
threeformulasdid not exhibitany evidenceof plntotoxicityin humars.Denatonium Benzoateis a bittersubstance
detectableat a concentration of 10 ppb, discerniblybitter at 50 ppb, and unpleasantly bitterat 10 ppm.The distribr.rtion
of
topicallyappliedlidocaine,a topicalanestheticchemicallyrelatedto DenatoniwnBenzoatedemorstratedthat virtuallyno
lidocaireappearsin the plasma,sqgestirg that the largerDenafonium Benzoatemoleculealsowouldhavelittleor no
$ystemicexposure.Denatonium Benzoate(0.1o/o)did not shovvadverseeffectsin 10 rats in an acuteinhalationtoxicitytest
and 0.005%to 0.05%was nonirritating to ocularmrrosa in 6 albinorabbits.The acuteoral LD(50)for the malerats was
640 mg/kg and for fernales,584 rngikg. The LD(50)for the mab rabbits was 508 mgftg and for the female rabbits, 640
mg/kg.In two chronictoxicitystudies,DenatoniumBenzoatewas administered(by gavage)at 1.6, 8, ard 16 mg/kg/day,
one rcirB cyromologtsmonkeysand the other rats, resuftedin no compound-related toxicity.The toxicityof SD Alcohols
has also beentested,with implications for the particulardenaturantrced. An irritationtest of 55.65%SD Alcohol40-B
denaturedwith Denatonium Benzoateusirg rabbitsproducedminimaleffects.A spray formulacontaining12YoSD Alcohol
4GB was foundto be nonirritating whenevaluatedfor wginal mucosalirritationin l,lewZealandwhite rabbits.Cosrnetic
formulatiorscontainingSD Alcohol40-B (denaturedwith Denatonium Berzoate)were not sersitizersin repeatedirsult
patchtests. A gel formulacontainirg29% SD Alcohol40-B ard a spray liquidcontainirg12oloSD Alcohol4G'Bdiri not
irtducephotoalbrgy, dermal sersitizatio[ or phototoxicresponsein hurnansubjects.Althor.ghthe absorptionof ethanol
(akaAlcoholfor purposesof cosnetic ingredientlabelirB)occursthroughskin,etharnldoes rpt appearto affec{tte
integri$of the skin barriernor reacha rcry highsystemiccorrcentration followingdermaleposure. Ethanolmay be fourd
in the bloodstreamas a resultof inhalationeposure and ingestion.Topicallyapplied,ethanolcan act as a penetration
enhancer.Most of the systemictoxicityof ethanolappearsto be associatedwith chronicabwe of alcohol.Although
ethanolis denaturedto makeit unfitfor consumption, there havebeenreportsof intentionaland unintentional consumption
of productscontainingdenaturedalcohol. Etlnrpl is a reprodrc{iveand delrelopnentaltoxicant. Ethanolis genotoxicin
some test systems and it has been proposedthat the genotoxlceffects of ethanolare mediatedvia its netabolile,

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 of Alcohol D... [Int J Toxicol.2008...
oftbe safetyassessnpnt hry:l/www.ncbi.nknnih.gov/puhrnd/18569I 6i

/ acetaldetryde.A brief swnmary is providedof the effects of chronicingestionof alcoholinclding intoxication,liver damage,
brain damage,and possiblecarcinogenicity.The CIR Erpert Panelrecogniresthat certain ingredientsin this grorp are
reportedlyrlsed in a gircn productcategory, but the concertrationof use is not arrailable.Becase dermal applicationor
inhalationof cosnreticproductscontainhg these ingredientswill rpt producesignificantsystemic elgosure to ethanol,the
CIR Expert Panelconchded tlnt safety of the irgredientsshouH be predicaled on the safety of the denaturantsused. The
Panelcprsidered that the adverseeffecis knownto be associatedwith Alcoholirgestion irnluded in this safety
assessrnert do not suggest a concernfor AlcoholDenat. or SD Abohob becarce of tln preseme of the denaturants,
which are added for the erpress purposeof makirg the Alcoholunpotable.The QIR Epert Panelhas previorsly
conduc{edsafety assessmentsof t-Br.tylAlcotpl, Dbttryl Phthalate,MettrylAlcohol,SalicylicAcid, Sodiun Salicylate,and
Methyl Salicylate,in which eadr was affinned safe or safe with qualificatiors.Giventheir use as denaturantsare at low
concer{fationsof tse in Alcohol,the CIR Epert Paneldeterminedthat AlcoholDenat.denaturedwith t-Butyl Alcohol,
DiettrylPtrthalate,MettrylAlcohol,SalicylicAcid, SodiumSalicylate,and MettqrlSalicylateis safe as used in cosnetic
formulationswith rp qualificatiors. Likewise,becarce they are denaturedwith either t-Bdyl Alcohol, DietlrylPlttnhte, or
MettrylAl@hol, SD Alcohols3-A, 30, 39''8, 394, and 4&C all are orsklered safe as used"The Parel corsidered the
arrailabledata for DenatoniumBersoate and SD Ahohol 4SB to be sufficientto slpport the safety of these irBredbnts in
cosnetics. DenatorriumBenaate is snfficientlybitter tlmt it is an effective denaturarf at only 0.0@6%. The Parel
recogniredthat data on dermal penetrationof DenatoniumBenrcate were rnt availabb, but corsidered that the available
data on lidocaine,a smalbr stnrturally related chemical,indicatesthat dermal eleosure does mt result in measurable
systemicerposure. Tte availabledata, howewr, were not snfficientto gryport tte safety of Quassin,Bnnire, and
BrucineSulfate,AlcoholDenat.denaturedwith those denaturaflts,or $D Alcohol39 and $D Alcohol40 (SD Alcohole
denaturedwith Quassin,Brrcine, and/or BnrcineSulfate), and in order for tJn Erpert Panelto reach a corclrcion for these
denaturants,additiorsl data are needed.

PMID:18569160 - indercdfor MEDLINE]

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