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Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38)
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INSECTICIDES CYPERMETHRIN & alpha-CYPERMETHRIN First draft prepared by Mrs Ir. M.E.J. Pronk, Dr G.J.A. Speijers, Mrs M.F.A. Wouters Toxicology Advisory Centre National Institute of Public Health and Environmental Protection Bilthoven, Netherlands Dr L. Ritter Canadian Network of Toxicology Centres University of Guelph Guelph, Ontario, Canada 1. 2. Explanation Biological data 2.1 Biochemical aspects 2.1.1 Absorption, distribution and excretion 2.1.2 Effects on liver enzymes 2.2 Toxicological data 2.2.1 Acute toxicity 2.2.2 Short-term toxicity studies 2.2.3 Long-term toxicity/carcinogenicity studies 2.2.4 Reproductive toxicity studies 2.2.5 Special studies on embryotoxicity and teratogenicity 2.2.6 Special studies on genotoxicity 2.2.7 Special studies on neurotoxicity 2.2.8 Special studies on biochemistry and electrophysiology 2.2.9 Special studies on sensitization 2.2.10 Special studies on skin and eye irritation 2.3 Observations in humans Comments Evaluation References EXPLANATION
3. 4. 5. 1.
Cypermethrin and alpha-cypermethrin are highly active synthetic pyrethroid insecticides, effective against a wide range of pests in agriculture, public health and animal husbandry. Cypermethrin has been widely used throughout the world since the late 1970s while alpha-cypermethrin has been available commercially since the mid 1980s. Cypermethrin and alpha-cypermethrin are neuropoisons acting on the axons in the peripheral and central nervous system by interacting with sodium channels in mammals and insects. Cypermethrin and alpha-cypermethrin have not been previously evaluated by the Committee. However, cypermethrin was reviewed by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) in 1979 and 1981 (FAO, 1980, 1982); an ADI of 0-0.05 mg/kg bw was established at the 1981 meeting. Studies reviewed in 1979 and 1981, which were not available at the present meeting were considered in this evaluation on the basis of the JMPR summaries.
879. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38)
Cypermethrin consists of eight isomers, four cis and four trans isomers, the cis isomers being the more biologically active. Depending on the manufacturing source, the cis:trans ratio varies from 40:60 to 80:20. In the studies submitted for evaluation the cis:trans ratio was in the range of 48:52 to 50:50. The purity varied between 92-95.1%. alpha-Cypermethrin contains more than 90% of the insecticidally most active enantiomer pair of the four cis isomers of cypermethrin as a racemic mixture.
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BIOLOGICAL DATA Biochemical aspects Absorption, distribution and excretion
According to the JMPR (FAO, 1980, 1982) cypermethrin is readily absorbed and rapidly eliminated via urine and faeces of mice, rats, dogs, sheep and cows. Absorption from the gastrointestinal tract is more rapid with the trans isomer than with the cis isomer. The highest mean concentrations are found in body fat, liver, kidney, muscle, skin and milk. The clearance rate from adipose tissue is slow and the elimination half-life in rats and mice ranges from 10 to 20 and from 20 to 30 days, respectively. The data suggest a potential for bioaccumulation in the body following continuous exposure. With respect to the chemical and especially the isomeric complexity of the molecule, the metabolic profile due to all of its isomers is extremely complex. Cypermethrin is readily cleaved at the ester linkage to produce the cyclopropane carboxylic acid and a 3-phenoxybenzoyl moiety that is further metabolised by oxidation at the 4'position. The resultant phenol is almost totally conjugated with sulfate. The 4'-hydroxy sulfate forms the major aryl metabolite (16%), and 3-phenoxybenzoic acid is the second most important (5%). The other identified aryl metabolites are 3-(4-hydroxyphenoxy)benzoic acid (1%) and the glycine conjugate, N-(3-phenoxybenzoyl) glycine (1%). 22.214.171.124 Rats
1. Selected fat samples were analysed for parent compound. the elimination of radioactivity was rapid. kidney and skin (application area) was measured.2% was recovered.4 Cattle a) Cypermethrin Two lactating Friesian cows were fed twice daily a diet containing 0. 25 and 42 days after dosing. When applied dermally radioactivity was slowly absorbed and eliminated.1. but were eliminated at a similar rate.25 mg/kg bw per day) in gelatin capsules in the diet. After 24 hours (sheep 1) and 6 days (sheep 2) the animals were killed. Another sheep was treated orally (single dose) with 177 mg 14Ccypermethrin mixture in a gelatin capsule (equivalent to 3.03 to 0. and radioactivity in fat.5% of the dose being eliminated in 6 days.5% was excreted in urine within 24 hours and only 2% over a 6-day period. kidney.5 mg cis-cypermethrin/kg bw.1. 1987). This radioactivity was composed of parent compound (0. 1977). One sheep treated with acetone served as a control. muscle.3 µg/g and muscle samples contained 0. Between days 14 and 42.2 Chickens Página 3 de 27 14C-benzyl-labelled 14C-phenoxy-labelled Six Warren laying hens were treated daily for 14 days with 10 mg cypermethrin/kg food (equivalent to 1. Residues in muscle (0.2 mg 14C-benzyl-labelled cypermethrin/kg feed. 2.9 mg/kg bw in acetone. Following oral treatment. highest radioactivity was found in the liver (0. 2. In liver.879. 14.3 Sheep Two male sheep were each treated dermally (single dose) with a mixture of 962 mg 14C-cypermethrin (both cyclopropyl. renal fat and subcutaneous fat (other than the application area). In muscle. Residues found in tissues were comparable to those found after dermal application.5 hours after the last dose.5%. liver and kidney was measured. 95. equivalent to 21. 61% of the administered radioactivity being eliminated within 48 hours. liver and kidney samples.06 µg/g. 1978). Most of the radioactivity in the fat samples of all sheep was found to be parent compound.1.37 µg/g).01-0. Most radioactivity was found in the yolk and was a mixture of parent compound and material that was closely associated with neutral lipids and phosphatidyl cholines. Urine and faeces were collected for 2 days and tissues were assayed.and benzyl-labelled).08 µg/g and about 60% of the residue was present as parent compound. Faecal elimination was also slow. Urine and faeces were collected up to the time the sheep were killed. muscle and fat samples were collected. In tissues. 90-100% of the radioactivity was in the form of the parent compound (Crawford & Hutson. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) Eight female Wistar rats were orally dosed with 2. Cow I . only a small percentage of the total tissue radioactivity was identified as parent compound (Crawford & Hutson. Residues in liver and kidney were 30 to 40 times lower than those in fat. 0. They were killed in groups of two at 8.9 mg/kg bw).1. and liver. The hens were killed 4. Of the total radioactivity. In two pooled fat samples taken 8 and 24 days after dosing.1. Fat contained 0. Radioactivity in eggs plateaued 8 days after the start of dosing and reached 0. About 30% of the applied radioactivity was recovered from the application areas of both sheep.02 µ/g) were too low for characterization (Hutson & Stoydin.09 to 0. residues ranged from 0.05 µg/g) and a mixture of very polar metabolites that were not hydrolysed to significant amounts of 3-phenoxybenzoic acid or its 4-hydroxy derivative. Very little radioactivity was found in the tissues. Urinary elimination comprised 41% of the dose and faecal elimination 20.05 mg/kg. and the radioactivity in fat. Eggs and excreta were collected dally. Less than 0. liver. radioactivity was eliminated from the fat with a half-life of 20-25 days. 2.
07 µg/g.8%. The liver and kidney metabolites were hydrolysed in hot acid to 3-phenoxybenzoic acid and its 4'-hydroxy derivative (Croucher et al. Milk. Total recovery of the radioactivity was 97.027 µg/g. The major proportion (93%) of the milk .11 µg/g) > fat (0.009 µg/g.6% for the cow dosed with benzyl-labelled cypermethrin. Radioactivity in milk was < 0. Urinary excretion accounted for 23% of the dose and milk less than 1%. The major route of excretion was via the urine (54%) and faeces (43%). A third cow was treated similarly with 14C-benzyl-labelled cypermethrin.2%. 3-phenoxybenzoylglycine (16%) and 3-phenoxybenzoic acid (9%). Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) was treated for 20 days and cow II for 21 days.006 µg/g. Analysis of milk revealed that the radioactivity was due to unchanged cypermethrin.004 µg/g. The cow was killed 16 hours after the last dose and samples of fat.01 µg/g). blood and brain were less than 0. Urinary excretion accounted for about 49% of the dose while faecal excretion accounted for about 38%. Total recovery of radioactivity was 92. The major route of excretion was similar for both label compounds. accounting for 34% of the total administered dose. An equilibrium between ingestion and excretion was reached after 3-4 days.21 µg/g) > kidney (0.2 mg/kg by day 4 of dosing. fat and muscle were analysed for radioactivity. urine and faeces were collected daily for radioassay. Total radioactive residues in milk accounted for 0.879.04 µg/g) > muscle (0. muscle. bile 0. The radioactivity in milk. A control cow was maintained under identical conditions. The major route of excretion of radioactivity was via the faeces. faeces. Liver contained 0. Very low levels of radioactivity were determined in milk (0. An untreated cow was held as control. Total recovery was 93%.10 µg/g). milk. 3-(4-Hydroxyphenoxy)benzoic acid and its O-sulfate conjugate appeared to be present in only small amounts (1%) (Crawford. respectively). The radioactivity in the milk.1 µg/g) > blood (0.13 µg/g and renal and subcutaneous fat 0. kidneys.4% for the cows dosed with cyclopropyl-labelled cypermethrin and 89. and 3-(4-hydroxyphenoxy) benzoic acid O-sulphate. Milk contained 0. Radioactivity in liver and kidney was due mainly to N-(3-phenoxybenzoyl)glutamic acid. Urine.003-0. brain 0. (The overall calculated daily dietary concentrations were 19 and 14 mg/kg. the minor metabolite (ratio 4:1).013 µg/g).014 mg/kg on day 2 and rose to 0. renal fat 0. 1978). which was located mostly in the lipophilic components (cream or butterfat). The residue in fat was largely unchanged cypermethrin. 1980). liver. major organs and tissues were analysed for radioactivity. major organs and tissues were analysed for radioactivity. 14C-benzyl-labelled Página 4 de 27 One lactating cow was administered a diet containing 10 mg cypermethrin/kg feed twice daily for 7 days. urine and faeces was measured daily and after 20-21 days of dosing the cows were sacrificed and blood. The animals were killed 6 hours after the last dose. Another cow received the same dose of unlabelled alphacypermethrin. Two lactating Friesian cows were fed twice daily for 7 days a diet containing 5 mg 14C-cypermethrin (cyclopropyl-labelled)/kg feed.005 µg/g. Radioactivity in tissues was generally in the order: liver (0. b) alpha-Cypermethrin One lactating cow received orally 125 mg 14C-alpha-cypermethrin (benzyl labelled)/dose twice daily for 4 consecutive days (target dose 250 mg/day). liver.011 µg/g and subcutaneous fat 0.. tissues (muscle. kidney 0. urine and faeces was measured daily.5% of the dose. the major metabolite. kidney 0. The urinary metabolites included the glutamic acid conjugate of 3-phenoxybenzoic acid (68%). The residues in muscle. After 7 days of dosing the cows were killed and their blood. 1976). In faeces 36% was eliminated as unchanged parent compound (Hutson & Stoydin. The urinary metabolites were tentatively identified as N-(3-phenoxy-benzoyl)glutamic acid. blood. A control cow was maintained under identical conditions. Radioactivity was rapidly eliminated in equal proportions in the urine and faeces. liver and kidney were analysed.
879. Surviving animals recovered within 7 days (Rose. These signs of toxicity appeared within a few hours following dosing. tremor and clonic convulsions. owing to great inter-animal variation. 800. The total PNOD activity of liver was also increased (30%). fat and milk contained mainly a single component (muscle 85%. Cypermethrin-induced signs of toxicity were typical of cyano-containing pyrethroid intoxication. which in each case had similar chromatographic properties to alpha-cypermethrin. Urinary metabolites were analysed using HPLC. 400. 0. and survivors recovered within 3 days. The activity of hepatic p-nitroanisole o-demethylase (PNOD) was determined in each of these rats. 1976). Morrison & Richardson. The kidney extract contained at least nine metabolites with a broad range of polarities. 1980). tip-toe walking. 1993.39 and 0..03 mg/kg residues. At 800 mg/kg some animals had ungroomed coats and abnormal gait. choreoathetosis. alpha-Cypermethrin-induced clinical signs. are typical of cyano-containing pyrethroid. PNOD activity. Body weight (gain) was dose-relatedly decreased in mice at 1200 and 1600 mg/kg and in females . Mice at 1200 and 1600 mg/kg developed ungroomed coats.43. fat 91% and milk 97% of the exact profile). In male rats treated with cypermethrin. 2.1 Toxicological data Acute toxicity Acute toxicity studies of cypermethrin and alpha-cypermethrin are summarized in Tables 1 and 2. Muscle. Treated females exhibited increases in PNOD activity when expressed per gram of liver (21%) and per whole liver (39%).56.1. 1200 or 1600 mg alpha-cypermethrin/kg feed for 29 days.2.2. The liver extract contained at least eight metabolites with a broad range of polarities. piloerection. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) residues was confined to the cream fraction. lacrimation. Plasma contained 0. renal fat. omental fat. was significantly increased (38%). 0. One component (16%) had similar chromatographic properties to alpha-cypermethrin. tip-toe walking. but only the latter was significant (Potter & McAusland. respectively). statistical significance was not reached. like those of cypermethrin. subcutaneous fat and kidney (0.1 Short-term toxicity studies Mice Groups of eight mice (CD-1)/sex received diets containing 0.08 mg/kg and muscle samples contained < 0.2 2.2. A minor component (3%) had identical chromatographic properties to 3-phenoxybenzoic acid (Dunsire & Gifford.2. The liver and kidney contained a range of components.22 mg/kg. 2. and increased salivation. After oral administration signs of intoxication included sedation. 1983).2 Effects on liver enzymes Página 5 de 27 Six Wistar rats/sex were randomly selected from each of the control and 1000 mg cypermethrin/kg food group at termination of a 2-year feeding study. 1994). one component (20% of the profile) had similar chromatographic properties to alphacypermethrin. but. Residues in tissues were highest in liver. These animals showed neurological disturbances. The two major components (44% and 20%) had identical chromatographic properties to N-(3-phenoxybenzoyl)glutamic acid and N-(3-phenoxybenzoyl)glycine.48. splayed gait. respectively. abasia.2 2. The observed signs included ataxia. One male fed 1600 mg/kg and one female fed 1200 mg/kg were killed in a moribund condition. with occasional tremors and convulsions. 2. over-activity or hunched posture. expressed as per gram of liver. The acute toxicity after dermal administration is of a low order (Coombs et al. ataxia. 1982b. 0. ataxia/abnormal gait. gait abnormalities. 200.
. Hb. Urea levels were increased in all dosed males and females. A similar. total WBC and leucocyte counts were decreased. No histological changes were observed. In females relative liver weight was increased at 250 and 1000 mg/kg and relative brain and spleen weight at 1000 mg/kg. Relative lung weight was increased in males at 1600 mg/kg. Four males at 1000 mg/kg died during week 12 probably due to stress of treatment and refusal of food and water. No effects were found in haematological. 25. a NOEL was not identified (Amyes et al. hair loss and encrustations in males at 250 mg/kg and hair loss in two males at 50 mg/kg. 1982a Rose. Relative liver weight and blood urea levels were increased at the highest dose level (only a summary available) (Coombs et al. 1982a Rose. nervousness and incoordinated movement from week 2 onwards. adrenal. 1976 Rose. Food consumption was slightly higher in mice at 1000 mg/kg. spleen.1% 98. In males at 1000 mg/kg.. 1982a Coombs et al. liver. equal to 57 mg/kg bw per day (Green. lung and testes weight were increased. The NOEL was 400 mg/kg feed. The relative kidney weights of these animals appeared to be slightly higher. Overall food conversion efficiency of animals receiving 1000 mg/kg (and to a lesser extent 250 mg/kg) was lower than that of controls. Serum AP was increased in females at 1000 mg/kg. groups of six rats/sex (Charles River) received diets containing 0. heart. 100. 1982a . and glucose was decreased in males at 1000 mg/kg. 1993). Plasma albumin and A/G ratio were decreased in males at 1600 mg/kg.2 Rats Página 6 de 27 a) Cypermethrin In a 5-week feeding study.1% 98.879. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) at 800 mg/kg. susp. Clinical signs included thin build.1% ? 98. macroscopic or microscopic examinations. Two males and eleven females treated at 1000 mg/kg were considered to be emaciated at necropsy. Groups of 12 mice (CD-1)/sex received diets containing 0. In males at 1000 mg/kg relative brain. Owing to the hair loss seen at 50 mg/kg. rats developed piloerection. food intake and terminal body weight were all reduced for both sexes at 1500 mg/kg. RBC. but less marked effect was apparent in males receiving 800 mg/kg and females receiving 400 mg/kg.2. 5% in corn oil Rose. 1200 and 1600 mg/kg. Food consumption was lowered in rats at 1200 and 1600 mg/kg during the first 2 weeks. 50.2. ungroomed coat. 750 or 1500 mg cypermethrin/kg feed. One mouse at 250 mg/kg died.. PVC. ALAT and ASAT levels were increased in males at 1600 mg/kg. without clear dose relation. hair loss and encrustations of the dorsal body surface in animals receiving 1000 mg/kg. 250. Body weight gain. Acute toxicity of cypermethrln in animals Species1 Route Purity2 LD50 mg/kg bw Remark Reference Mouse Mouse Mouse Mouse Mouse oral oral oral oral percutan. No macroscopic or microscopic effects were seen. Urinary specific gravity was increased in mice at the highest dose level. ASAT was increased in a dosedependent manner in males at 250 and 1000 mg/kg. In the highest dose group. ungroomed haircoat in mice at 250 mg/kg. kidney. 250 or 1000 mg alpha-cypermethrin/kg feed for 13 weeks. 98. 1976).1% 88 82 1126 657 > 100 5% in corn oil 5% in corn oil 40% in DMSO 50% aq. A depression in lymphocyte numbers was noted in males receiving 1600 mg/kg. Body weight gain was markedly lower in mice at 1000 mg/kg and lower in mice at 250 mg/kg. Table 1. 2. Relative kidney weight was increased in males at 800. 1994).
100. Species1 Route Purity (%) LD50 mg/kg bw or mg/m3 Remark Reference Mouse Mouse Mouse Mouse Rat Rat Rat Rat Rat oral oral oral percut. ? . 1982a Rose. 1976 1 2 Both male and female animals were used in all of the studies cis:trans isomer ratio 51:49. susp.. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) Rat Rat Rat Rat Rat Rat Rat oral oral oral oral percutan. i.unknown Acute toxicity of alpha-cypermethrin in animals Table 2.. MCV and eosinophil counts. CMC 40% in DMSO 50% aq.6 96. 1982b Gardner. 25. 1982b Rose. oral oral oral dermal inhal 96. conc. This could be attributed to the palatability of the diet. 400 or 1600 mg cypermethrin/kg feed for 91-95 days. and an increase in prothrombin time.1% ? ? ? ? 251 4000 3423 > 2000 > 2000 > 1600 approx. 1976 Rose. b) alpha-Cypermethrin .1% 98. 40% in xylene 40% in corn oil Página 7 de 27 Coombs et al. During week 13. 1993 1 Both male and female animals were used in all of the studies Groups of 12 rats/sex (Wistar) were fed diets containing 0 (24 rats/sex). 1976 Coombs et al.6 techn.. 1976 Coombs et al. 1984 Price.6 96. There were no deaths. In males at 400 mg/kg there was also a decrease in eosinophil numbers. females at 1600 mg/kg had reduced food intake.6 96.. 1993 Rose. The mean plasma urea concentration in the 1600 mg/kg groups was increased. 500 5% in corn oil 40% in DMSO 50% aq. 1993 Jackson. 1982b Rose. suspension undiluted as aerosol (MMAD 9 µm) Rose.. no clinical signs and no macroscopic or microscopic changes. Relative liver weight was increased in males and females at 1600 mg/kg and in males at 400 mg/kg.6 96. Relative kidney weight was increased in males at 1600 mg/kg. 1982b Gardner. 95. 1982b Rose. techn. ? 98. suspension 5% in corn oil 50% aq.p. Males at 1600 mg/kg showed decreases in Hb.6 35 762 798 > 100 64 4000 > 5000 > 2000 1590 5% in corn oil 40% in DMSO 50% aq. 1982b Rose. The NOEL was 100 mg/kg feed.6 techn. equivalent to 5 mg/kg bw per day (Pickering. In the highest dose group a reduced body weight gain was observed. conc. 2600 203 approx.879. percutan. During the first week reduced food consumption was observed in both sexes at 1600 mg/kg. 1981). 1982a Price. techn. 96. 1976 Hamster Guinea-pig oral oral ? ? 5% in corn oil 20% in corn oil Coombs et al. 1984 Coombs et al.
200. relative spleen. 20.879. Microscopic examination revealed lymphocytolysis and iymphocyte depletion of the cortical region of the thymus in males fed 800 mg/kg and males and females at 1200 mg/kg (Fokkema. clinical chemistry. splayed gait. 60. All rats at 1200 mg/kg and all males at 800 mg/kg were killed during weeks 2 to 4 because of severe clinical signs. equivalent to 10 mg/kg bw per day (Thorpe. total leucocyte count and absolute values of polymorphic neutrophils and lymphocytes were increased. clinical signs. abasia and hypersensitivity. owing to signs of severe neurological disturbance. Histopathological investigations showed a solitary form of axonal degeneration. affecting the fibre only. liver and kidney weights were increased. one from controls and one at 540 mg/kg were removed because of severe skin lesions. MCV and MCHC were decreased in females at 540 mg/kg. and macroscopic and microscopic lesions. 200. The number of lymphocytes was increased and the number of eosinophils was decreased in males at 540 mg/kg. In both sexes at 540 mg/kg relative kidney weight was increased and relative liver weight was increased in both sexes at 180 and 540 mg/kg. One male at 800 mg/kg that was removed from the study showed scanty axonal lesions of the sciatic nerves. Cachexia was seen in extreme cases. Observations included mortality. 100. One male at 800 mg/kg died unrelated to treatment and two males at 800 mg/kg were killed. urinalysis. Both sexes at 800 mg/kg produced abnormal gait and increased sensitivity to noise. but there were no clinical signs of toxicity. heart and brain weights were increased. in two males fed 540 mg/kg. The mean body weights and food intake of both males and females fed 400 or 800 mg/kg were significantly lower than those of controls. 800 or 1200 mg/kg feed for up to 6 weeks. Three males at 540 mg/kg developed an abnormal gait consisting of splayed hind limbs. Groups of 30 male and 30 female Wistar rats received diets containing 0 (60 rats/sex). The MCV was decreased at 200. In males at 800 mg/kg the kaolin-cephalin coagulation time was increased and the percentage of polymorphic neutrophils was increased at 800 mg/kg. in the sciatic nerve. In both males and females at 800 mg/kg and in males at 400 mg/kg prothrombin time was increased. 400 or 800 mg alpha-cypermethrin/kg feed for 5 weeks. In a range finding study groups of five male and five female rats were fed diets containing a-cypermethrin at concentrations of 0. The NOEL was 200 mg/kg feed. Abnormal gait was seen in one male at 400 mg/kg. organ weight. After 6 weeks 10 rats/sex (controls 20/sex) were sacrificed for interim examinations. Food consumption was lower at 60 mg/kg than at 180 mg/kg. AP was decreased in females at 180 and 540 mg/kg. The NOEL was Página 8 de 27 . During the second part of the study. 50. Urinary volume was decreased in females at 540 mg/kg and specific gravity was increased in males and females at 540 mg/kg. At termination the Hb value was decreased in males and females at 540 mg/kg. Two males. haematology and clinical chemistry and microscopy. Relative testis weight was increased in males at 540 mg/kg. No effects were found on food consumption. In females fed 540 mg/kg. In females at 800 mg/kg relative brain. Skin sores and fur loss were observed in all males with the highest incidence at 540 mg/kg and in females at 0 and 540 mg/kg. haematology. but not in a clearly dose-related manner. These females also had a lower leucocyte count. 1982). There were no significant changes in fore or hind limb grip strength or hind limb landing foot splay. 180 or 540 mg alphacypermethrin/kg feed for 90 days. body weight gain was also reduced in males at 60 and 180 mg/kg. Reduced body weight and reduced food consumption were seen in rats at 540 mg/kg. These signs included high stepping. Relative brain. Platelet counts were increased in males and females at 540 mg/kg. In females platelet count. liver and kidney weights were increased in males fed 800 mg/kg and relative brain and liver weights were increased in males fed 400 mg/kg. Urea concentration was increased in females at 540 mg/kg. 1994a). 400 and 800 mg/kg but not in a dose-related manner. Female rats fed 800 mg/kg had a lower mean body weight and food intake compared to controls. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) Groups of 10 Wistar rats/sex received diets containing 0 (20 rats/sex). body weight and food consumption. 20. but the Hb and haematocrit values were decreased.
liver weight or following microscopic examination. inappetence. because of the lack of a doseresponse relationship. 1982). haematology. Relative thyroid weight and blood urea levels were increased and blood glucose levels were decreased (only a summary available) (Coombs et al. clinical chemistry.2. 2.2. No effects were found on body weight. Also a reduced food intake and body weight gain was seen. 5 days/week for 3 weeks. A pink colour of the optic disc was noted in ophthalmological examinations..4 Dogs a) Cypermethrin In a 5-week feeding study. food consumption. Due to the clinical signs two dogs/sex at 1500 mg/kg had to be killed. The NOEL was 20 mg/kg bw (Henderson & Parkinson. diarrhoea and vomiting. and the fact that there were no changes in the prothrombin time.2. ataxia. this finding is not considered to be relevant. In the first part one male and one female beagle dog were fed alpha-cypermethrin in the diet at concentrations of 200 mg/kg feed for 7 days. A further experiment was undertaken to determine the cause of the pink discoloration. Cypermethrin was fed to two groups of three male dogs at concentrations of 0 or 500 mg/kg food for 13 weeks. 150 or 1500 mg cypermethrin/kg feed. Due to severe intoxication of the animals receiving 400 mg/kg. dosing was discontinued after 2 days. Minor variations in haematology were observed. 1981). b) alpha-Cypermethrin This study was conducted in two parts. The NOEL was 500 mg/kg feed. Specific ophthalmological examinations were made to evaluate the degree of coloration of the optic disc. No mortality occurred. 15. 20 or 200 mg cypermethrin/kg bw in PEG 300 were made to abraded and intact skin of groups of 10 male and 10 female NZW rabbits/sex. licking and chewing of the paws. 50. In the highest dose group dogs developed signs of intoxication. anorexia and tremors as well as ataxia. which occurred in all groups. including apprehension. No effects were observed on haematology. Slight to severe skin irritation was observed in rabbits at 200 mg/kg bw and slight to moderate skin irritation was observed in rabbits receiving 2 and 20 mg/kg bw. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) 60 mg/kg feed. 2.2. 400 mg/kg feed for 2 days and 300 mg/kg feed for 7 days. whole body tremors. the variability of this parameter throughout the study. At the end of 13 weeks. The applications were made for 6 h/day. equivalent to 3 mg/kg bw per day (Clark. Dogs at 1500 mg/kg developed diarrhoea. clinical chemistry or following macroscopic or microscopic examination. Decreased food consumption and body weight gain was observed in rabbits treated with 200 mg/kg bw. ophthalmoscopy. After the third week . and decreased body weight gain. 5. Absolute and relative gonad weights were reduced in male rabbits at 200 mg/kg bw.3 Rabbits Página 9 de 27 Occluded dermal applications of 0. groups of three beagle dogs/sex received diets containing 0. 1977). incoordination and hyperaesthesia. equivalent to 12. Microscopic examination of tissues and organs revealed a non-specific focal bronchopneumonia in the lungs of the dogs at 1500 mg/kg. macroscopy.5 mg/kg bw per day (Buckwell & Butterworth. However. 500 or 1500 mg/kg feed for 13 weeks. 1976).879. 2. The animals were fed the control diet and in week 3 treatment was commenced at 300 mg/kg. a stiff exaggerated hind leg gait. the kaolincephalin clotting time was consistently lower throughout the study in female dogs at 500 mg/kg. No effects were seen on clinical chemistry parameters or on organ weights. Groups of beagle dogs (four/sex) were fed cypermethrin (purity 98%) in the diet at concentrations of 0. there were no consistent differences between the colour of the optic discs of the treated dogs and the controls (Buckwell & Butterworth. 1977).
Ten mice/sex were killed after 52 weeks for interim necropsy.2. At interim kill and at termination.2 Rats Groups of 48 Wistar rats/sex received diets containing 1. The NOEL was 90 mg/kg. No effects were observed on body weight. 400 or 1600 mg cypermethrin/kg feed for up to 101 weeks. equivalent to 1. food consumption. 60. respectively. Four groups of beagle dogs (four/sex) received via the diet 0. were found in the 1600 mg/kg group at the interim kill. One female at 270 mg/kg was killed.2. clinical chemistry.2. food consumption. and no changes were observed in macroscopic or microscopic examinations.3. 100 or 1000 mg cypermethrin/kg feed for 2 years. haematology.5 mg/kg bw per day (Dean & Jackson. subdued behaviour. haematology. haematology. organ weights or microscopy were seen. poor limb coordination. 2. including body tremors. SPF-Swiss-derived) received diets containing 0 (2 groups). 12 and 24 rats/sex). head nodding. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) the dogs were killed.. Observations included mortality. 90 or 270 (six dogs/sex) mg alpha-cypermethrin/kg feed for 13 weeks. ataxia. Abdominal skin reddening and alopecia were seen in another male at 240 mg/kg and one female at 120 mg/kg. The NOEL was 60 mg/kg feed. In the second part one male and one female beagle dog were fed alpha-cypermethrin in the diet at 300 mg/kg food for 3 days (male dog) or 4 days (female dog). No effects on mortality. All dogs at 270 mg/kg developed marked clinical signs. 100. Several haematological changes. The control group consisted of 96 rats/sex and was fed untreated diet for 2 years. body weight gain. clinical chemistry. body weight. and macroscopy and microscopy. At 250 mg/kg only the female dog developed the clinical signs shown by the dogs treated with 300 and 400 mg/kg (Greenough & Goburdhun. clinical signs. ataxia. 1995).3 2. equivalent to 2. Clinical signs including ataxia. Groups of four beagle dogs/sex received diets containing dose levels of 0. but not at termination. ophthalmoscopy. Body weight loss was observed at 300 mg/kg. consistent with mild anaemia. lip licking. head nodding.879. 2. 30. Two males at 240 mg/kg developed skin reddening on the tail. 1982). urinalysis or organ weights.. 1984). ophthalmoscopy. Examination of the cellular composition of blood and the chemical components of plasma showed no abnormalities. clinical chemistry.3. food consumption. The tail reddening caused obvious irritation and resulted in ulceration and necrosis in one male leading to amputation of part of the tail. 120 or 240 mg alpha-cypermethrin/kg feed dally for 52 weeks. Body weight gain of both males and females at 1600 mg/kg was reduced when compared to the combined control groups. 10.25 mg/kg bw per day (Greenough et al. equal to 57 mg/kg bw per day (Lindsay et al. organ weights. No dose-related effects were observed on mortality. haematology. After 6 and 12 months six rats/sex were sacrificed and after 18 months 12 rats/sex were sacrificed (controls. subduedness.1 Long-term toxicity/carcinogenicity studies Mice Página 10 de 27 Groups of mice (70/sex. inflamed gums and elevated temperature. . The only effects observed were reductions in body weight and food consumption in males and females at 1000 mg/kg. An increase in the incidence of benign alveologenic tumours was observed in females at 1600 mg/kg. macroscopy. body tremors. food regurgitation. 1984). an increase in thrombocytosis and absolute and relative liver weight was seen in males at 1600 mg/kg. and then 250 mg/kg food for 7 days. and no macroscopic changes were observed. but was within historical control incidence. At 300 mg/kg the same effects were obtained as above. In this study the NOEL was 400 mg/kg feed. diminished response to stimuli and inflammation of gums and tongue were obtained when dogs were dosed with 300 and 400 mg/kg. clinical chemistry. agitation and high stepping gait. because of severe head and body tremors.
These signs were observed at 1000 mg/kg and to a lesser extent at 750 mg/kg. In the satellite group no effect on body weight gain was seen.3 Dogs Página 11 de 27 Groups of four beagle dogs/sex (5´-7 months of age) were fed diets containing 0. when signs of intoxication persisted during weeks 6-8. the dogs were fed cypermethrin at a concentration of 600 mg/kg food for the remainder of the study.4 Reproductive toxicity studies Groups of 30 rats/sex (Wistar) received diets containing 0. 2. 300 or 1000 mg cypermethrin/kg food for 2 years. Males and females from the second litter were randomly selected to breed the next generation. 100 and 500 mg cypermethrin/kg feed for 5 weeks prior to mating and then throughout pregnancy and lactation for three successive generations. equivalent to 5 mg/kg bw per day (Hend et al. 10. This was correlated with a reduction in food consumption. The NOEL for maternal and reproduction toxicity was 100 mg/kg feed. macroscopy or microscopy. the concentration was reduced to 750 mg/kg at week 4 of the study and. head shaking. equivalent to 5 mg/kg bw per day (McAusland et al. 2. convulsions.2. 17.879. Signs of intoxication appeared within 24 hours of the initiation of dosing and consisted of licking and chewing of the paws. 300 or 1000 mg/kg cypermethrin (data concerning this satellite group have only been included in the report to aid interpretation of the results of the main study). a stiff high stepping gait.1 Special studies on embryotoxicity and teratogenicity Rats a) Cypermethrin Groups of 25 pregnant female rats (Sprague-Dawley) received by gavage 0. probably due to initial reduction in food consumption observed at 1000 mg/kg. No abnormalities were found in the sciatic nerves.5 2. One female at 70 mg/kg bw per day was found dead and one female at 70 mg/kg bw per day was killed for ethical reasons following severe convulsions. Following the 10 days of control diet. Fish.5. No difference between control and treated groups were found in the sciatic nerves. litters on days 7. organ weights. organ weights.. A significant reduction in body weight gain was seen in the male and female parent rats receiving 500 mg/kg in all three generations. The body weights of male dogs in the highest dose group were significantly lower than the controls. Apart from some occasionally decreased sodium levels in the males given the highest dose. 14 and 21 of lactation. 2. 1981). whole body tremors. ataxia and.2. equivalent to 7. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) clinical chemistry. One male dog in the satellite group fed 1000 mg/kg convulsed and died. No other effects on fertility or reproduction parameters were found. 35 or 70 mg cypermethrin/kg bw per day in corn oil during days 6 to 15 of gestation. The NOEL was 100 mg/kg feed. hypersensitivity to .5. Eleven out of 25 females at the 70 mg/kg bw per day group showed neurological disturbances (ataxia. No effects were observed on ophthalmoscopy. Litter size was reduced at 500 mg/kg in the F1a litter at birth and after 7 and 21 days. Due to severe signs of intoxication observed at the 1000 mg/kg level. Thorpe. macroscopy or microscopy. 1978).3. 1978.5 mg/kg bw per day (Buckwell. Groups of four dogs/sex were allocated to a satellite study and received a diet containing 0.2. There was no increase in compound-related tumours. 1985).. The first litters were discarded at weaning. Litter weights were reduced at 500 mg/kg in the F1a. 1979.2. The females were sacrificed on day 21 of gestation for examination of their uterine contents. in some cases. but not at 600 mg/kg. Two litters were bred per generation. animals in the high-dose group were fed a control diet for 10 days to allow them to recover. no consistent haematological changes were seen. brain or spinal cord. 3. incoordination. clinical chemistry. convulsions. The NOEL was 300 mg/kg feed. 30.
by gavage. After treatment with 18/15 mg/kg bw per day a lowered body weight gain and food consumption was seen. At 9 mg/kg bw per day a slight body weight reduction was seen. live young and resorptions. The number of implantations. 15 or 18 mg alpha-cypermethrin/kg bw in corn oil during days 6-15 of gestation. Necropsy revealed evidence of respiratory tract infection and/or gastrointestinal tract infection not related to the substance. Four dams at 18 mg/kg bw per day and one dam at 15 mg/kg bw per day showed hindlimb splay and unsteady gait during dosing.5. A dose-related reduction in body weight gain was observed in the groups given 35 and 70 mg/kg bw per day. In another study. 50. limb splay and hypersensitivity to sound. After reduction of the dose level the signs were similar but less marked. The fetuses were weighed. Mean body weight gain was reduced in a dose-related manner at 9. body weights and food consumption were recorded. Mean fetal weights were slightly reduced at 18/15 mg/kg bw per day. piloerection. sexed and examined for external. 1984b.879. Live fetuses were . The NOEL for maternal toxicity was 17. Following marked clinical signs of toxicity the dose level of 18 mg/kg bw per day was lowered to 15 mg/kg bw per day on day 10 of gestation. 10 or 30 mg/kg bw per day orally from days 6 to 18 of gestation.5 mg/kg bw per day and the NOEL for embryotoxicity was 70 mg/kg bw per day (Tesh et al. Clinical signs. b) alpha-Cypermethrin In a range-finding study.and post-implantation losses.6%)/kg bw per day in corn oil during days 6-15 of gestation. On day 20 of gestation the females were killed and necropsied. 1994c).2 Rabbits Página 12 de 27 a) Cypermethrin In a range-finding study. 9. Two females at 20 mg/kg bw per day and two females at 120 mg/kg bw per day aborted during the post-treatment phase of the investigation.. On day 28 of gestation the rabbits were killed and examination was made of live fetuses. On day 20 of gestation the females were killed and the fetuses were weighed. five pregnant female Sprague-Dawley rats received daily. Groups of 16 pregnant NZW rabbits received by gavage 0. 9 or 18 mg alpha-cypermethrin (purity 95. 1978). 3. The NOEL for maternal and fetal toxicity was 9 mg/kg bw per day (Irvine. 50 or 120 mg cypermethrin/kg bw per day in corn oil during days 6 to 18 of gestation. 20. Females at 18 mg/kg bw per day showed unsteady gait. 30 rabbits were used as an additional control group) were administered cypermethrin dissolved in corn oil at dose levels of 0. Maternal body weights. Groups of pregnant rabbits (20 rabbits/group. There were no indications of any embryotoxic or teratogenic effects. dead fetuses.. 2. 3. and fetal and placental weights were unaffected by treatment. There was no indication for teratogenicity. The dams were killed on day 29 of gestation. food consumption and clinical observations were recorded. 3.2. 25. visceral and skeletal abnormalities. 1994). The dams were sacrificed on day 29 of gestation.. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) noise). No adverse effects were seen in the mothers and fetuses (Tesh et al. resorption sites and corpora lutea. 100 or 120 mg cypermethrin/kg bw per day in corn oil. groups of 24 pregnant female Sprague-Dawley rats received by gavage 0. 1984a). 15 and 18 mg/kg bw per day and at 15 and 18 mg/kg bw per day food consumption was reduced. 1988). The NOEL for embryo-toxicity was 120 mg/kg bw per day (Tesh et al. 0. No other treatment-related abnormalities were observed (Irvine & Twomey. pre. One control female. sexed and externally examined. There was no indication for embryotoxicity or teratogenicity. three females receiving 20 mg/kg bw per day and two females in each of the groups receiving 50 and 120 mg/kg bw per day were killed for ethical reasons. groups of four female pregnant rabbits (NZW) received during days 6 to 18 of gestation by gavage 0.
Tip-toe walking was also seen in some rats. At 30 mg/kg bw per day there was a further reduction in mean body weight gain towards the end of the dosing period. Food consumption reflected the changes in mean body weight gain. There were no significant differences between control and test groups with respect to pregnancy. 2. Histological examination revealed swelling of the myelin sheaths and breaks of some of the axons of the sciatic nerves. Fetuses were also examined for gross somatic and skeletal deformities. Two control females. At 400 mg/kg bw. The females were killed on day 28 of pregnancy. The rats were then killed and examined histologically.2. 15. 1994a). 2. including controls. In a neuromuscular dysfunction test. which continued until day 11.7. within 4 hours of dosing. Although a wide range of skeletal and visceral abnormalities was found in the course of the study. spasmodic movements of the body and tail and bleeding from the nose. At 100 mg/kg bw all animals survived the 9 days. implantations and live fetuses were counted. The fetuses were weighed. 1976). There was no significant mortality or difference in weight gain during the period of gestation. In another study.2. The NOEL for maternal toxicity was 3 mg/kg bw per day and the NOEL for embryotoxicity was 30 mg/kg bw. were killed. 3. One female out of 12 showed minimal lesions in the sciatic nerve in this group. Wistar rats (10/sex) were . 25 or 30 mg a-cypermethrin/kg bw per day as solutions in corn oil. there was a similar mean body weight loss after the onset of dosing. because of severe weight loss and low food consumption. fetal death and survival. The remaining four rats survived the observation period. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) maintained for 24 hours to assess viability. The fetuses were weighed. there were no differences between control and test groups with respect to abnormalities. three at 15 mg/kg bw per day and two at 30 mg/kg bw per day were killed. The observation period was 9 days. All rats showed signs of intoxication.2. At 200 mg/kg bw similar effects were observed. One female at 15 mg/kg bw aborted on day 28. At 25 and 30 mg/kg bw per day marked reductions in body weight and food consumption were seen. body weight and food consumption were recorded. eight rats of each sex died or were killed within 48 h of dosing. Maternal clinical signs. There was no indication for teratogenicity (Irvine. On day 28 of pregnancy the females were killed and a necropsy was performed. There was no indication for either embryotoxicity or teratogenicity (Irvine. sexed and externally examined. during days 7-19 of gestation. In all groups. 1980). The uterus was weighed and the numbers of corpora lutea. rats developed signs of intoxication. including coarse tremors.6 Special studies on genotoxicity Página 13 de 27 Results of genotoxicity studies carried out cypermethrin and alpha-cypermethrin are summarized in Tables 3 and 4. All animals.1 Special studies on neurotoxicity Rats a) Cypermethrin Groups of 6 or 12 rats/sex were administered single oral doses of 100. visceral and skeletal abnormalities. sexed and examined for external. 15 or 30 mg alpha-cypermethrin/kg bw per day in corn oil during days 7-19 of gestation. It was concluded that oral dosing up to 30 mg/kg bw during the major period of organogenesis resulted in no teratogenic effects in offspring (FAO. groups of 16 pregnant NZW rabbits received by gavage 0. 200 or 400 mg cypermethrin/kg bw (purity 97%) as a 5% dispersion in corn oil.7 2. One female each at 15 and 25 mg/kg bw per day was killed prematurely. 5. owing to the severity of the signs. b) alpha-Cypermethrin In a range finding study groups of five mated female NZW rabbits received by gavage 0.879. A NOEL could not be determined (Carter & Butterworth. except one. 1994b).
1979 ? negative Wistar rats negative Creedy Wooder 1977 Cree Wood . 16 hour exposure ? negative Dean. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) treated by gavage with 0. 1981 Gene mutations assay Mitotic gene conversions assay Host-mediated assay in mice Cell transformation assay Chromosomal aberrations assay 0. f 150 mg/kg. 50. 1981 RL4 liver cells 7. 1. 100.5 negative Dean. TA98. 25.25. Results of mutagenicity assays on cypermethrin (cont'd). 1977 Host-mediated assay DNA damage assay mouse/ S. and right and left sciatic/posterior tibial nerves were analysed. cerevisiae CD rats ? negative JMPR. Test system Test object Concentration Purity (%) Results Refere In vivo Chromosome aberration assay in bone marrow Dominant lethal assay Chinese hamster 2x oral dose of 20 or 40 mg/kg bw (2 successive days) single oral dose of 6.5-30 µg/ml 93. cerevisiae JD1 25 and 50 mg/kg bw 93. 16 hour exposure m 300 mg/kg.5 or 25 mg/kg bw or 5 daily doses of 2. TA100. 1981 Table 3.5 negative S.0 mg/litre1 93.01-5. 1981 Dean. Neuromuscular function was assessed by means of the inclined plane test and peripheral nerve damage by reference to ß-glucuronidase and ß-galactosidase activity increases in nerve tissue homogenates. 50 mg/kg m 100 mg/kg. The rats were killed 3-4 weeks after the start of dosing. 1981 Dean. Results of mutagenicity assays on cypermethrin Página 14 de 27 Test system Test object Concentration Purity (%) Results Refere In vitro Gene mutations assay S. 1977 mouse ? negative Dean et al. 4.5 negative Brooks 1980 BHK 21/C113 cells 31.5 or 5 mg/kg bw per day orally 0.coli WP2 or WP2 uvrA Saccharomyces cerevisiae JD1 0. 1.5 negative2 93.25-250 µg/ml1 93. 25. 12. TA1537 E. Table 3. 4.2-2000 µg/plate1 93.879. 150 or 200 mg cypermethrin/kg bw per day in DMSO for 7 consecutive days.5 negative Dean. TA1538. typhimurium TA1525.5 negative2 Brooks 1980 Dean.2-2000 µ/plate1 0.
. cerevisiae XV185-14C L5178Y mouse lymphoma cells human peripheral lymphocytes 31. 20 or 40 mg/kg were used. coli WP2 uvrA S.5 mg/kg. but the animals exhibited severe signs of toxicity and the experiment was terminated at these doses. Results of mutagenicity assays on alpha-cypermethrin (cont'd). 1 hour exposure f 337. 4 and 16 hour exposure Página 15 de 27 1977 1 2 with and without metabolic activation at 200 and 2000 µg/plate. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) f 450 mg/kg.25-4000 µg/ml 3.5% of the females died. typhimurium TA98. Surviving females were evaluated for chromosomal damage and none was observed At 200 mg/kg bw per day 50% of the males and 62.6 negative (no toxicity) B W 1 Gene mutations assay1 Gene mutations1 assay Chromosomal aberrations assay1 31.879.6 negative precipitation was seen B W 1 In vivo Chromosomal aberrations rat femoral bone marrow single oral dose 2-8 mg/kg3 95.8 negative B 1 95. TA1537 TA1538 E. formation of visible droplets in the top agar was seen Results of mutagenicity assays on alpha-cypermethrin Table 4.4 negative V 1 -act: 93.4 negative V 1 rat 96. No mortalities occurred in the other groups.75-1000 µg/ml +act: 125-1000 µg/ml 95.3-50 µg/ml 95. TA100. Test system Test object Concentration Purity (%) Results R In vitro Gene mutations assay1 S. at 150 mg/kg bw per day two females and one male died and at 100 mg/kg bw per day one female died but no males.8 negative C W 1 Table 4. A dose-related (in severity and duration) increase was seen in clinical signs at doses > 100 mg/kg bw. 6 hours exposure 95.5 negative W 1 With and without metabolic activation The effect of alpha-cypermethrin on the integrity of rat liver DNA was investigated by this method Initially doses of 10.5-5000 µg/ml 95. Test system Test object Concentration Purity (%) Results R Micronucleus assay Alkaline elution analysis assay2 1 2 3 mouse single oral dose 1-10 mg/kg bw single oral dose 40 mg/kg. TA1535.
including cypermethrin. The NOEL was 4 mg/kg bw (Fokkema. gait abnormalities and clinical signs of increased reactivity were seen in most male rats dosed with 20 and 40 mg/kg bw. Cypermethrin was administered at 150 mg/kg bw per day in DMSO (reduced to 100 mg/kg bw per day in arachis oil. 4. hindlimb landing foot splay and motor activity. The signs included abnormal/ splayed gait. fine tremors of low intensity and fluid loss. hyperactivity. hunched posture. The intersession interval was one week. During the 14-day observation period. 0. ataxia. The first phase was conducted to determine the time course for neurochemical changes in Wistar rats occurring in the sciatic/posterior tibial nerve (SPTN). The effects of some pyrethroids. tremor and choreoathetosis. piloerection. In females the signs were less frequent. hyperexcitability to auditory stimuli. nerves. soft faeces and thinning of the fur.879. In the 20 and 40 mg/kg bw groups there was a increase in very slight to slight sporadic fibre degeneration in the sciatic nerve. 1983). At the same dose levels body weight gain was also reduced. clinical signs and body weight were analysed. 20 or 40 mg alpha-cypermethrin/kg bw in corn oil. The groups received a single dose of 0. significant increases in ß-glucuronidase and ß-galactosidase were found 3-4 weeks after the start of dosing in the distal portion of the sciatic/posterior tibial nerves.5. on amplitude and pre-pulse inhibition of the acoustic startle reflex were studied in male Wistar rats. Clinical signs were seen in male rats dosed with 20 and 40 mg/kg bw. Animal behaviour was observed by the experimenter before and after the test session for a period of 10 minutes and the effects of the pyrethroids on overt behaviour were measured by scoring the presence of pawing and salivation. This included a functional observational battery (FOB) and measurements of fore and hind limb grip strength. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) These signs included salivation. Neither cypermethrin nor the other pyrethroids tested affected the amplitude or the latency of the startle reflex (Hijzen et al. spinal cord and spinal ganglia were analysed. muscle. The signs in females were similar but lower in frequency. Each animal received all doses of cypermethrin. Página 16 de 27 . soiled/stained body areas and diarrhoea. thrashing. trigeminal nerve and trigeminal ganglion following treatment with cypermethrin for 5 days/week for 4 weeks. unkempt appearance. hyperreactivity to an external stimulus. after 10 doses. vocalization. The pyrethroids were suspended in corn oil. In each study five rats/sex were killed on day 15 and brain. The changes were more frequent in the proximal than in the distal part of the nerve. One male rat in each of the 20 and 40 mg/kg bw groups of the additional study was found dead on the day after dosing. burrowing. In addition to these signs there were also isolated cases of twitching. 1994b). tremors. abasia. each using four groups of ten animals/sex or five rats per sex (additional study). The NOEL was 50 mg/kg bw per day (Rose & Dewar. prostration. The signs (similar in both studies) developed between 3 to 8 hours after dosing and resolved by three days after dosing. pale eyes. There was no direct correlation between the time course of the neuromuscular function and the neurobiochemical changes. A dose-related transient functional impairment was found in rats treated with cypermethrin in the inclined plane test. 1 or 2 mg/kg bw to 12 males. During FOB conducted 5 hours after dosing. Cypermethrin was given orally at dose levels of 0. eyes. 1988). splayed hind limb gait. At doses which caused mortality. In the main study a detailed clinical assessment for neurotoxicological effects was performed. b) alpha-Cypermethrin The acute neurotoxicity of alpha-cypermethrin was studied in Crl:CD:BR rats in two separate acute studies. hypersensitivity. because of mortality). This effect was maximal at the end of the 7-day subacute dosing regimen.. c) Cypermethrin and alpha-cypermethrin This experiment was performed in two phases.
1977).7.5 mg/kg bw cypermethrin and 10 mg/kg bw alpha-cypermethrin (Rose. Histological examination of these animals showed lesions in the cerebellum. were killed at 2. and after 12 weeks was comparable to controls. trigeminal nerve and ganglia. 5. After 3 weeks the dosing regime was repeated and a further three weeks later the birds were killed. Lower body weight gain was . The magnitude of the enzyme changes was similar to those of phase 1. 10 or 12 weeks and examined. six adult domestic hens received 1000 mg cypermethrin/kg bw per day in DMSO for 5 days.879. All birds receiving the positive control developed clinical signs of neurological damage within 15 days and became progressively more unsteady and ataxic thereafter. Hamsters treated orally with doses of 5. and a marginal increase in ß-galactosidase was observed in peripheral nerve. As in the cases of rats. Significant enzyme changes were also found in the trigeminal ganglia and to a lesser extent in the trigeminal nerve of the groups administered 75 or 150 mg/kg bw per day cypermethrin and 20 or 40 mg/kg bw per day alpha-cypermethrin.2. all treated hamsters showed clinical signs of poisoning. 1980) evaluated some neurotoxicity studies with cypermethrin in hamsters. The lesions included swelling and breaks in the axons and clumping of myelin. treated with either cypermethrin and alpha-cypermethrin. A positive (tri. chromodacryorrhoea.7. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) alpha-Cypermethrin was dosed at 37.2. In the groups administered 75 mg/kg bw per day cypermethrin or 20 mg/kg bw per day alpha-cypermethrin a small increase in ß-galactosidase was found in both the distal and proximal sections of the SPTN. 3. Chickens Página 17 de 27 In a delayed neurotoxicity study. including axonal and myelin degeneration (Owen & Butterworth.5 mg/kg bw per day in DMSO (also reduced after 10 days to 25 mg/kg bw per day in arachis oil). 6. 5 days/week for 4 weeks. Histological examination of the nervous system revealed no lesions. At doses of > 794 mg/kg bw. 4. abnormal irregular movements and an unusual gait. ataxia.ortho-tolyl phosphate) and negative control (not dosed) group were used. A control group of 10 animals was used. salivation and hypersensitivity to sensory stimuli. 6 and 8 weeks. 2. The ß-glucuronidase and ß-galactosidase activities in the SPTN were increased at 5. Five animals per sex. A large increase in ß-glucuronidase and ß-galactosidase activities in the SPTN was seen at 150 mg/kg bw per day cypermethrin and 40 mg/kg bw per day alpha-cypermethrin. Hamsters treated orally with a single dose of 40 mg/kg bw. 10 or 20 mg/kg bw per day for 5 days showed no mortality. 75 or 150 mg cypermethrin/kg bw per day in DMSO or 10. Groups of 10 rats/sex were dosed with 37. lethargy. There was loss of fur and dermal ulceration. The NOELs were 37.5. developed weight loss and sometimes mortality. 8. followed by four doses of 20 mg/kg bw. axon and myelin degeneration was noted in all groups treated. 1983). The increase was maximal after 5 weeks. There was no effect in the mean slip angle experiment.3 Hamsters The 1979 JMPR (FAO. when compared to controls. The most frequent signs of intoxication included abnormal gait. Dosing resulted in the death of 56% of the cypermethrin-treated animals and 21% of the alpha-cypermethrin-treated animals. None of the cypermethrin-treated hens developed any signs of intoxication. 20 or 40 mg alpha-cypermethrin/kg bw per day in DMSO.2. 2. sciatic nerve and spinal cord. No significant enzyme changes were found in the trigeminal ganglia and trigeminal nerve of treated animals. Signs of intoxication similar to those reported in phase 1 were seen at the highest dose levels. including tremors. Phase 2 was conducted to establish the dose level which did not cause peripheral nerve degeneration in the SPTN.
One female (out of 5) at the highest dose developed hyperexcitability. ß-Galactosidase activity was increased at all dose levels 3 weeks after the onset of the experiment. 10% in DMSO) on the trigeminal ganglion and three sections of the maxillary branch of the trigeminal nerve (proximal. ß-Glucuronidase activity was increased in a dose-dependent fashion in both males and females. but even in the most severely intoxicated animals the magnitude of this increase was less than that induced by the known neurotoxic agent methylmercury chloride (Dewar & Moffett. In this experiment dermal irritation and fur loss were noted. A dose-related functional deficit was observed when the mean slip angle test and the landing foot spread test were applied to the animals. These electro-physiological findings are reflective of motor function. 2. One male (out of 16) had an unusual gait. The three studies involved repeated oral administration of cypermethrin at 150 mg/kg bw per day for 5 or 7 days and 0. Data were inconsistent over the course of the study. 1980). The results suggested that cypermethrin produced a primary axonal degeneration. This effect was significant at the two highest dose levels. which would suggest that the physiological and functional deficits observed as a result of . The deficit was maximal from days 6 to 14 after the beginning of treatment. There was no evidence to suggest that cypermethrin.8 Special studies on biochemistry and electrophysiology Página 18 de 27 In three independent experiments with Wistar rats the effects of varying doses of cypermethrin (purity 98%. readily measurable 28 days after treatment as an increase in ß-glucuronidase activity and in deficits in specific behavioural-function testing of rats (FAO. including ataxia. Electrophysiological studies were performed to determine whether acute or subacute intoxication with cypermethrin produced changes in the conduction velocity of slower fibres in peripheral nerves or alterations in the maximal motor conduction velocity. Mortality occurred in animals receiving 100 mg/kg bw per day or more. There was a significant deficit in the mean slip angle test. and complete functional recovery occurred within 4 weeks. Cypermethrin (1:1 cis:trans) was administered to male and female rats at dose levels ranging from 25 to 200 mg/kg bw per day for 5 consecutive days by oral intubation as a 10% w/v solution in DMSO. There was a slight deficit in the inclined plane test which was noted in the early parts of the experiment. A dose-related transient functional impairment.2. tibial or trigeminal nerves only occurred with 5 or 7 doses of 150 or 200 mg/kg bw per day. Increased activity of the enzymes in the distal portion of nerves was found. females showing an earlier dose-related deficit than noted in males. had any effect on maximal motor conduction velocity or conduction velocity of the slower motor fibres in peripheral nerves. distal and endings) were determined. 1978).879. 100 or 200 mg/kg bw per day for 5 or 7 days. 25. There was no mortality and there were no differences in weight gain. In another experiment hamsters were orally treated with 30 mg/kg bw per day for 5 days. at doses that induced severe clinical signs of intoxication. Doses used in the study ranged from a single dose of 200 mg/kg bw to 7 consecutive doses of 150 mg/kg bw followed by two doses of 400 mg/kg bw. Increases in both ß-glucuronidase and ß-galactosidase were evident in peripheral nerve tissue. Significant increases in ß-glucuronidase and ß-galactosidase activity of the sciatic. Substantial variation in data from the landing foot spread test was noted. Increases in ß-galactosidase activity in these tissues were taken as evidence of axonal degeneration. 50. There was some transient skin irritation accompanied by skin ulceration. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) observed at 20 mg/kg bw per day. assessed by means of the inclined plane test was found in the first week. At near-lethal doses there were no effects on conduction velocity even in the presence of clinical signs of acute intoxication and at dose levels where previous studies had shown functional degeneration.
1993).05 µg/ml). 2. The more serious cases developed coarse muscular fasciculations in large muscles or extremities (Van den Bercken & Vijverberg. Vomiting was more prominent in patients with ingestive poisoning than in occupational poisoning cases. Systemic symptoms included dizziness.9. blurred vision and increased sweating were less frequently seen.9. The rate of dermal exposure of the operators during spraying ranged from 1. Cypermethrin sprayers were found to have residues on the exposed parts of their bodies. which could be exacerbated by sweating or washing and readily disappeared after several hours.2 alpha-Cypermethrin Six NZW rabbits receiving a semi-occlusive topical application with 500 mg alpha-cypermethrin technical developed very slight erythema in two animals up to 72 hours after removal of the dressings. 1989). indicating that cypermethrin is not a sensitizer (Coombs et al. Urine obtained from operators spraying cypermethrin in experimental trials was analysed for the presence of the chlorinated cyclopropane carboxylic acid metabolite. No cornea or iris irritation was observed (Gardner.3 Observations in humans The symptoms and signs of acute poisoning resulting from pyrethroids are very similar. This metabolite was observed in the urine of exposed workers at levels up to 0. nausea. He et al.. There was a reasonable relationship between the total cypermethrin deposited dermally and the excretion in urine. 1976). 2. 1993).1 Special studies on sensitization Cypermethrin Página 19 de 27 Two out of 20 guinea-pigs developed a positive reaction to cypermethrin in the Magnusson Kligman test.2.10. This.9 2. palpitation. Occupationally exposed people had abnormal skin sensations described as burning.2. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) acute intoxication are primarily sensory in nature (FAO.2...1 ml (equivalent to 45 mg) alpha-cypermethrin technical developed slight conjunctival redness and ocular discharge up to 72 hours after treatment.2. 1989. Six NZW rabbits receiving an instillation of 0. Apart from the irritative symptoms of the skin and respiratory tract (or digestive tract in ingestive poisoning). acute pyrethroid poisoning is clinically characterized by abnormalities of nervous excitability. 1976). A single application of undiluted technical cypermethrin to rabbit eyes produced a mild transient conjunctivitis and blepharism lasting 2 days (Coombs et al. together with the finding of 0. The levels of the cyclopropane carboxylic acid metabolite in the 24-hour urine were between <0. 2. itching or tingling. 1980).2 alpha-Cypermethrin No positive reactions were obtained in a Magnusson-Kligman test performed with guinea-pigs (Gardner.1 mg/hour.32 mg (not specified). paraesthesia. headache. 1976).879.4 µg/ml (the limit of detection was estimated to be 0.6 mg (not specified) of this metabolite in 72-hour urine from one man. 2.. There were no other dermal reactions (Gardner.05 and 0.10. 1993). anorexia and fatigue. led . Other symptoms such as chest tightness.10 2.2. 2.1 Special studies on skin and eye irritation Cypermethrin A single application of undiluted technical cypermethrin was moderately irritant to occluded rabbit skin (Coombs et al.5 to 46.2.
chickens. is cleavage of the ester bond followed by hydroxylation and conjugation of the cyclopropyl and phenoxybenzyl portions of the molecule. Cypermethrin is primarily eliminated in urine and faeces in about equal proportions. nervousness. In these studies. In some electroneurophysiological tests (motor conduction velocity. and studies on pharmacokinetics and metabolism. In a controlled experiment with sprayers. In rats and mice. WHO has classified these substances as "moderately hazardous" (WHO. Several oral short-term toxicity studies with cypermethrin were available. sheep and cattle.25-80 mg/kg bw per day) and 5 to 1500 mg/kg feed (equivalent to 0. at lethal or near-lethal doses. Studies in cattle indicated that absorption. alpha-Cypermethrin is a mixture of the two most active cis isomers. causing a long-lasting prolongation of the normally transient increase in sodium permeability of the membrane during excitation. inappetence. 2. Cypermethrin is a mixture of four cis and four trans isomers. blood chemistry or peripheral nerve function tests (including the trigeminal nerve). COMMENTS Página 20 de 27 The Committee considered toxicological data on cypermethrin and alpha-cypermethrin. effects on the nervous system. The cis isomers are more biologically active and more persistent than the trans isomers. the clinical signs included ataxia. They affect nerve membrane sodium channels. 1996). food intake. and.5 mg/kg bw per day).5% was eliminated in urine and faeces within 6 days and after an oral dose about 60% was eliminated within 2 days.and post-exposure measurements. 100. genotoxicity. Cypermethrin has been tested in rats (5 weeks and 90 days) and dogs (5 weeks and 13 weeks) at dose levels ranging from 25 to 1600 mg/kg feed (equivalent to 1. long-term toxicity/carcinogenicity and neurotoxicity. slow fibre conduction velocity and cornea reflex). and.879. and a number of haematological parameters. the oral LD50 ranges from 82 to 4000 mg/kg bw for cypermethrin and from 35 to > 5000 mg/kg bw for alpha-cypermethrin. After oral administration. no abnormalities were found in clinical and neurological examinations.125-37. At lethal or near lethal doses the signs are typical of type-II pyrethroids and include salivation. 3. including the results of acute. respectively. A typical cypermethrin sample contains 25% alphacypermethrin. a significant change within the normal range appeared to exist for the group sprayers between pre. When cypermethrin was applied dermally to sheep. In both rats and dogs. gait abnormalities and convulsions. distributed and excreted in rats. 400 or . including alpha-cypermethrin. The data suggest that there is no isomeric interconversion during metabolism. distribution and excretion were comparable for cypermethrin and alpha-cypermethrin. particularly in dogs. vomiting and hyperaesthesia. Results of effects in humans were also considered. The acute oral toxicity of cypermethrin and alpha-cypermethrin is moderate to high. increases in some organ weights and plasma urea levels. At high dose levels. Less than 1% is excreted in milk. depending on the vehicle used. diarrhoea. cypermethrin is readily absorbed. short-term. The major metabolic route for both cypermethrin and its isomers. 1980). these type II pyrethroids induce salivation and tremors that progress to characteristic clonic-tonic convulsions (choreoathetosis and salivation syndrome). abnormal gait. cypermethrin caused decreases in body weight gain. These changes probably reflect seasonal variations (FAO. For cypermethrin the lowest NOEL in short-term studies was in a 90-day study with rats administered 25. 1982). Cypermethrin and alpha-cypermethrin are alpha-cyano or type II pyrethroids that cause neurotoxicity in mammals and insects. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) to the estimation that approximately 3% of the total dermal dose was absorbed and rapidly excreted by the operators (FAO. ataxia. and reproductive studies.
abnormal gait. the only effects observed were reductions in body weight and food consumption at 1000 mg/kg feed. The NOEL in this study was 1. respectively. axonal degeneration of the sciatic nerves.879.5 and 9 mg/kg bw per day for cypermethrin and alpha-cypermethrin. Cypermethrin and alpha-cypermethrin have been tested in a wide variety of in vitro and in vivo genotoxicity studies. Cypermethrin did not cause embryotoxicity or teratogenicity in rats at doses up to 70 mg/kg bw per day or in rabbits at doses up to 120 mg/kg bw per day. In these studies. while the NOELs for maternal toxicity in rabbits were 30 and 3 mg/kg bw per day for cypermethrin and alpha-cypermethrin. rats (5 weeks. The NOEL was 100 mg/kg feed. 100 or 500 mg/kg feed (equivalent to 0. The NOELs for maternal toxicity in rats were 17. and increases in prothrombin time.25-60 mg/kg bw per day) and 30 to 270 mg/kg feed (equivalent to 0. A three-generation reproductive toxicity study with cypermethrin was performed in rats at dose levels of 10.075-25 mg/kg bw per day). Two long-term toxicity/carcinogenicity studies with mice and rats were available on cypermethrin. equal to 57 mg/kg bw per day. 300 or 1000 mg cypermethrin/kg feed (equivalent to 0. hyperactivity. respectively.75-6. Página 21 de 27 . At 300 mg/kg feed. 20 to 1200 mg/kg feed (equivalent to 1. equivalent to 5 mg/kg bw per day. dogs received diets containing 3. All of the results were negative. plasma urea levels and relative liver and kidney weights. The dose level of 1000 mg/kg feed was reduced to 600 mg/kg feed owing to severe intoxication. In female rats. 120 or 240 mg/kg feed (equivalent to 1.25-80 mg/kg bw per day). Dogs given 120 and 240 mg/kg feed showed skin reddening. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) 1600 mg/kg feed (equivalent to 1. as demonstrated histologically. No other effects on fertility or reproduction parameters were observed. In a study in which rats received diets containing 1. The NOEL in this study was 100 mg/kg feed. ulceration and necrosis. alpha-Cypermethrin was tested in oral short-term toxicity studies with mice (29 days and 13 weeks). The Committee concluded that cypermethrin was not carcinogenic in these studies. 10. respectively. The NOEL was 100 mg/kg feed. At the highest dose a reduction in body weight gain and food consumption and a concomitant reduction in litter size and weight were seen in the F1a progeny only. Mice received a diet containing 100. changes in haematological parameters and increased liver weight were observed. alpha-cypermethrin caused the same effects as described for cypermethrin in the short-term studies. equivalent to 5 mg/kg bw per day. equivalent to 5 mg/kg bw per day. In this study a diet containing 60.5 to 6 mg/kg bw per day) was administered. increased sensitivity to noise. alpha-Cypermethrin did not cause embryotoxicity or teratogenicity in rats at doses up to 9 mg/kg bw per day or in rabbits up to 30 mg/kg bw per day. For alpha-cypermethrin the lowest NOEL was in a 52-week study with dogs. hunched posture and. 6 weeks and 90 days) and dogs (13 weeks and 52 weeks) at dose levels ranging from 50 to 1600 mg/kg feed (equivalent to 7-240 mg/kg bw per day). equivalent to 7. Male rats given 1600 mg/kg feed showed decreases in haemoglobin concentration.5 mg/kg bw per day. In a two-year toxicity study. The decrease in eosinophil numbers and increase in relative liver weight were also observed in males at 400 mg/kg feed.75 mg/kg bw per day). mean corpuscular volume and eosinophil numbers. 100 or 1000 mg/kg feed (equivalent to 0. 400 or 1600 mg/kg feed (equal to 14-228 mg/kg bw per day) for 101 weeks. No effects were observed at 400 mg/kg feed. At 1600 mg/kg feed reduced body weight gain. 30.5-25 mg/kg bw per day). The signs of toxicity included ataxia. no effects were seen.05-50 mg/kg bw per day) for 2 years.5 mg/kg bw per day. reduced food intake and increased relative liver weight were noted in rats given 1600 mg/kg feed.
Irving. In these studies high oral doses of cypermethrin and alpha-cypermethrin caused clinical signs that included coarse tremor and spasmodic body and tail movements. Several studies on the neurotoxicity of cypermethrin and alpha-cypermethrin in rats were available. NJ..879. T. & Sparrow. T. SBTR. S. Unpublished report . 2-year and reproductive toxicity studies in rats and the application of a safety factor of 100.022 from Shell Research Limited. followed by systemic effects such as dizziness. FASTAC TM: In vitro chromosome studies using cultured human lymphocytes. Brooks.M. & Wiggins. (1984). USA.80. REFERENCES Amyes. Unpublished report No. Wayne. However. In view of the foregoing.. Green. Brooks. T. (1993). SBGR.F.92. NJ. T. D. D.. Sittingbourne Research Centre. nausea. Brooks. (1994). 5. (1980). Toxicity studies with agricultural chemicals: Mutagenicity studies with RIPCORD in microorganisms in vitro and in the host-mediated assay (Experiment Nos 1846 and 1847). In the inclined plane test. 4. Brooks.M. Humans occupationally exposed to cypermethrin developed skin sensation as a first reaction. Holmes. Wayne. & Wiggins.M.E. The Committee also noted the absence of genotoxicity for either cypermethrin or alpha-cypermethrin. Alpha-cypermethrin: preliminary toxicity study by dietary administration to CD-1 mice for 13 weeks. Wayne. Submitted to the WHO by Cyanamid.M. D.5 mg/kg bw per day in a 52-week study in dogs and the application of a safety factor of 100. Wayne. NJ. S. NJ. (1992). Unpublished report No. C. which contains 25% alphacypermethrin. Suffolk.. the Committee concluded that it was unnecessary to request the results of long-term toxicity/carcinogenicity or reproductive toxicity studies on alpha-cypermethrin.E. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) Long-term toxicity/carcinogenicity or reproductive toxicity studies were not available on alpha-cypermethrin. muscular fasciculations developed in large muscles or in the extremities. Submitted to the WHO by Cyanamid. Unpublished report TLGR. paraesthesia and increased sweating.M. 92/SHL009/0849 from Pharmaco-LSR Ltd.. In more serious cases. P. Evidence of axonal damage in the sciatic/posterior tibial nerves and the trigeminal nerve and ganglion was indicated by significant increases in ß-glucuronidase and ß-galactosidase in nerve tissue homogenates.059 from Shell Toxicology Laboratory (Tunstall). Sittingbourne Research Centre. headache. EVALUATION Página 22 de 27 The Committee established an ADI of 0-50 µg/kg bw for cypermethrin on the basis of the NOEL of 5 mg/kg bw per day in 90-day. indicating that the toxicity may be influenced by the vehicle used. USA. Submitted to the WHO by Cyanamid.J. Submitted to the WHO by Cyanamid. Virgo.117 from Shell Research Limited. the absence of carcinogenicity associated with compounds of similar structure and the similar metabolism and disposition of the two compounds. The lowest NOEL for neurotoxicity was 37. in addition to abnormal neuromuscular function tests. Genotoxicity studies with Fastac: the induction of gene mutation in the yeast Saccharomyces cerevisiae.5 mg/kg bw per day for cypermethrin (in DMSO) and 4 mg/kg bw per day for alpha-cypermethrin (in corn oil). E. The Committee noted the absence of reproductive toxicity and carcinogenicity associated with administration of cypermethrin. USA. exposure levels were not measured. USA.M. The Committee established an ADI of 0-20 µg/kg bw for alpha-cypermethrin on the basis of the NOEL of 1. In experiments with operators spraying cypermethrin. no clinical nervous system abnormalities were observed. FASTAC TM: Bacterial mutagenicity studies. cypermethrin (in DMSO) caused transient functional impairment. Unpublished report No.84. England.
J. Wayne. Toxicity studies with agricultural chemicals: In vitro genotoxicity studies with RIPCORD (Experiment Página 23 de 27 .77 from Shell Toxicology Laboratory (Tunstall). Submitted to the WHO by Cyanamid. 1112). USA. Dean. NJ. SBGR.76 from Shell Research. NJ. Unpublished report No. Carter. (1977). Wayne. Buckwell. Wayne. NJ..0136. SBGR. Unpublished report No. NJ.J. Wayne.81. Unpublished report No.M. The metabolic fate of cypermethrin in the cow: elimination and residues derived from 14C-benzyl label. (1980). A. M. NJ. S.B. Submitted to the WHO by Cyanamid.007 from Shell Research Limited.81.0055. NJ. Buckwell. B.879. & Wiggins. Submitted to the WHO by Cyanamid.J.. Crawford. (1976) Toxicity studies on the insecticide WL 43467: Summary of results of preliminary experiments. J. USA.I. USA. Unpublished report No.H. & Wooder. USA. M. Sittingbourne Research Centre.G. USA. Hend. Unpublished report No. WL85871: A 90-day feeding study in rats. The excretion and residues of radioactivity in cows treated orally with 14C-labelled WL 43467. Buckwell. TLGR. Crawford. NJ.93. M. Submitted to the WHO by Cyanamid. TLGR. (1977).0043.G.H. TLGR. TLGR. Wayne. M. Stoydin. Unpublished report No. (1976).E. D. Unpublished report No.76 from Shell Toxicology Laboratory (Tunstall). Toxicity of insecticides: The acute oral toxicity and neuropathological effects of WL 43467 to rats. TLGR. Toxicity studies with WL 43467: Chromosome studies on bone marrow cells of Chinese hamsters after two daily oral doses of WL 43467. NJ. Sittingbourne Research Centre. Submitted to the WHO by Cyanamid. (1981). Unpublished report No. USA.F. Toxicology studies on the pyrethroid insecticide WL 43467: a 13-week feeding study in dogs (Experiment No. B. Wayne.D.C. NJ.. D. Clark.0104. USA.E. Butterworth. B. (1981). D. (1982).. Wayne. Submitted to the WHO by Cyanamid. Clare. NJ. Cheeseman.78 from Shell Toxicology Laboratory (Tunstall). C. NJ.G. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) No.84. A. Wayne. Wayne. Crawford. Wayne. & Gellatly. S. Carter. TLGR.. Wayne. NJ. Submitted to the WHO by Cyanamid. Sittingbourne Research Centre. USA. TLGR. Submitted to the WHO by Cyanamid. G. Submitted to the WHO by Cyanamid. (1977). A.121 from Shell Toxicology Laboratory (Tunstall).77 (including addendum and corrigendum) from Shell Toxicology Laboratory (Tunstall).78 from Shell Toxicology Laboratory (Tunstall). Unpublished report No. NJ. The elimination and retention of WL 43467 when administered dermally or orally to sheep. A.C. The elimination of residues from the fat of rats following the oral administration of [14C-benzyl] WL 43381 (cis-WL 43467). & Butterworth. A 2-year feeding study in dogs on WL 43467 (Experiment No. Unpublished report No.0078. USA.77 from Shell Toxicology Laboratory (Tunstall). (1984). A.126 (plus two addenda) from Shell Toxicology Laboratory (Tunstall).J. D. Dean.293 from Shell Research Limited. A. USA.G.0098. Wayne. & Buckwell.. Unpublished report No. Sittingbourne Research Centre.C. M.0029. Submitted to the WHO by Cyanamid. & Butterworth. (1978).T.C. TLGR 0127.. SBTR. SBGR. Submitted to the WHO by Cyanamid.J. Unpublished report No. (1977) Studies on the effect of WL 43467 upon the integrity of rat liver cell DNA in vivo. Submitted to the WHO by Cyanamid. & Hutson.120 from Shell Research Limited. R.W. M. Wayne. & Hutson. TLGR. (1978). Genotoxicity studies with fastac: in vivo cytogenetic test using rat bone marrow. Creedy. USA.. USA. Coombs. Submitted to the WHO by Cyanamid. Croucher. B.80. S.I. 1412).L.77 from Shell Toxicology Laboratory (Tunstall). USA.
The distribution of [benzyl-14C]WL85871 (FASTAC) in the lactating cow (nature of residue study to EPA guidelines . Wayne. Submitted to the WHO by Cyanamid. Wayne. Unpublished report No. & Moffett. A. SBTR. (1984). USA. NJ.J. Wayne. IRI/9879 from Inveresk Research International. Wayne. R. Submitted to the WHO by Cyanamid. & Jackson. USA.93. Fokkema.. Toxicity studies with WL 43467: Dominant lethal assay in male mice after single oral doses of WL 43467.P. Food and Agriculture Organization of the United Nations (FAO Plant Production and Protection Paper. & Goburdhun. 20). Unpublished report No. G. & Goburdhun. Rome. NJ. Dunsire. Submitted to the WHO by Cyanamid. Greenough. WL85871: 52-week oral (dietary) toxicity study in dogs (IRI Project No. FAO (1982). Unpublished report No.92. skin and eye irritancy in rabbit and skin sensitisation potential in guinea pig.N. Pesticide residues in food-1979. TLGR. J. Gardner. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues.116 from Shell Toxicology Laboratory (Tunstall). R. R. (1979).J. WL85871 (FASTAC): A 6-week range finding feeding study in the rat. Rome. USA. Unpublished report No.033 from Shell Research Limited. NJ. WL 85871: Oral (dietary) maximum tolerated dose study in dogs (IRI Project No. Cockrill. NJ. Unpublished report No. Toxicity studies on the insecticide WL 43467: Biochemical studies on the effect of WL 43467 on the rat trigeminal nerve and ganglion. LSR 92/0346 from Life Science Research Limited. Scotland. Unpublished report No. A. Dewar. B. IRI/3107 from Inveresk Research International. USA. Submitted to the WHO by Cyanamid.002 from Shell Research Limited. & Butterworth S. 631087). USA. Unpublished report No. (1995). Alphacypermethrin: Preliminary toxicity study by dietary administration to CD-1 mice for four weeks.. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) No. F. Van der Pauw. WL85871 (FASTAC): An acute oral (gavage) neurotoxicity study in the rat. SBTR. Unpublished report No. (1994a). Fokkema.L.. (1977). NJ. NJ. (1993). 652238). Sittingbourne Research Centre. J.. USA. C.92. (1978). Wayne. Unpublished data from Shell Toxicology Laboratory (Tunstall). Wayne. & Gifford. Dean.J. USA. Sittingbourne Research Centre. NJ. Submitted to the WHO by Cyanamid. Submitted to the WHO by Cyanamid.77 from Shell Toxicology Laboratory (Tunstall).78. (1993). NJ.G. (1994b). I.0162. R. USA. AIR-1820).J. Submitted to the WHO by Cyanamid. Greenough. NJ.0042. Fish. L.T. NJ. Wayne.B. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues. 153667). Submitted to the WHO by Cyanamid.Live phase) (IRI Project No.J. SBTR. No. FAO (1980). WL 85871: 13-week oral (dietary) toxicity study in dogs (IRI Project Página 24 de 27 . Unpublished report No. NJ. Sittingbourne Research Centre. Submitted to the WHO by Cyanamid.027 from Shell Research Limited. Unpublished report No. Pesticide residues in food-1981.F. IRI/11110 from Inveresk Research International.879.N. USA. Corrigendum I in Group Research Report No. Food and Agriculture Organization of the United Nations (FAO Plant Production and Protection Paper. (1993). Scotland.0188.R. USA. FASTAC technical: Acute oral and dermal toxicity in rat. Wayne.80. No. B. Dean. 37). Submitted to the WHO by Cyanamid. Green. USA. TLGR. C.77 from Shell Toxicology Laboratory (Tunstall). (1984). Wayne. Wayne. G. Scotland. TLGR. Wayne. Submitted to the WHO by Cyanamid.J. TLGR. J.
Jackson. Cypermethrin: Lifetime feeding study in mice (CTL Study No. C. CTL/P/588 from ICI Central Toxicology Laboratory. USA. 4-hour exposure. Submitted to the WHO by Cyanamid. p. Chen. The excretion of radioactivity from cows fed with radioactively labelled WL 43467. USA. Clinical manifestations and diagnosis of acute pyrethroid poisoning. World Health Organization. Toxicol. USA.. M. Unpublished report No. Oral (gavage) rat developmental study. Submitted to the WHO by Cyanamid.. Oral (gavage) rabbit developmental toxicity (teratogenicity) study. NJ. P.H & Twomey. Unpublished report No. NJ. Wayne. Alphacypermethrin.T.H. PM0366).J. J. R. (1981). & Slanger. England. de Beun.F. (1993). (1978). P. NJ.C. Ledbury.S.H. SLN/1/92 from Toxicol Laboratories Limited.W. S.L. Wayne. Irvine. (1976). IRI/3197 from Inveresk Research International. Hutson. 631092).H (1994a).78 (including 4 corrigenda/addenda) from Shell Toxicology Laboratory (Tunstall). TLGR. S.3). CTL/P/687 (including 1 supplement) from ICI Central Toxicology Laboratory. Página 25 de 27 Henderson. Submitted to the WHO by Cyanamid. Chalmers. SLL 266/930770 from Huntingdon Research Centre. L. USA. Unpublished report No.F. 54-58...R. TLGR. USA. Hendy. NJ. Unpublished report No. L.H. T. Submitted to the WHO by Cyanamid. & Sun. Wang. USA. Ledbury.F. SLN/3/92 from Toxicol Laboratories Limited. S. Wayne. 63. (1988).. (1994). Cypermethrin technical: subacute dermal toxicity study in rabbits (CTL Study No.. Toxicity studies on the insecticide WL 43467: A two-year feeding study in rats. Toxicity studies on the WL 43367: a three generation reproduction study in rats.0189. L.76 from Shell Toxicology Laboratory (Tunstall). Irvine.J. Banham. 157-168. Oral (gavage) rabbit developmental toxicity dose ranging study. Excretion and residues of the pyrethroid insecticide cypermethrin in laying hens. Unpublished report No. Toxicology. England.H. D. & Stoydin.F. L. USA. Hijzen. Submitted to the WHO by Cyanamid. Godley... G. G. TLGR.. Wayne. Butterworth. Z.E. Submitted to the WHO by Cyanamid. NJ.879. 23 (Document WHO/PCS/96. S.B. Alphacypermethrin.78 from Shell Toxicology Laboratory Submitted to the WHO by Cyanamid. SLN/4/93 from Toxicol Laboratories Limited. 49. Wayne. Effects of pyrethroids on the acoustic startle reflex in the rat. Sci. SLN/2/92 from Toxicol Laboratories Limited. D. Wayne. Hutson. Ledbury. R. Hend. Wayne. insecticide Unpublished (Tunstall). Wayne. & Parkinson. & Stoydin. Unpublished report No. USA. (1982). G. USA.H. Unpublished report No. England. LB0019). Wayne.. Submitted to the WHO by Cyanamid.0075. McAusland. R. NJ. USA. & Fleming. NJ. F..G. NJ. (1994c). Unpublished report No. Scotland. NJ. & Hunt. (1994b). Wayne. Wayne. (1989). IPCS (1996) The WHO recommended classification of pesticides by hazard and guidelines to classification 1996-1997.F. J. Submitted to the WHO by Cyanamid. 271-276. Submitted to the WHO by Cyanamid. K. Geneva.. D. I. & Taylor. England. 18. Liu. Pestic.0188. Arch.... Lindsay. NJ.T. G. He. Unpublished report No. USA. Zhang. Alphacypermethrin: Acute inhalation toxicity in rats. K. Submitted to the WHO by Cyanamid. (1987). Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) No. H. England. Irvine. Unpublished report No. report No. D.. NJ. Oral (gavage) rat developmental toxicity (teratogenicity) study. (1978). . L. Irvine. Chart. Ledbury.
J. Submitted to the WHO by Cyanamid. FASTAC): The metabolism of 14C-WL85871 after repeated oral dosing in the lactating cow. & Wightman.W. NJ. NJ. Tesh. J. USA. USA. Rose. J. Technical concentrate (Project No. Toxicity studies on the insecticide WL43467: A study of liver microsomal enzyme activity in rats fed WL 43467 for 2 years (Experiment No. Dosage range finding study. Ross. USA. A 90-day feeding study of WL 43467 in rats (Experiment No. USA..130 from Shell Research Limited.M. G. (1977). Wayne. Toxicology of pyrethroids: the acute oral and percutaneous toxicity of WL 85871 (cis-2-Ripcord) in comparison with Ripcord. Potter. TLGR.82. SBTR. USA. J. Rose. & Davies.G. H. T.G. Wayne. Submitted to the WHO by Cyanamid. F. SBGR. Wayne. England. Sittingbourne Research Centre. 1806). NJ. & Wightman. Rose. SBGR. Submitted to the WHO by Cyanamid.879. Unpublished report of Life Science Research. Wayne. Submitted to the WHO by Cyanamid.P.P. Wayne. Ross. Intoxication with four synthetic pyrethroids fails to show any correlation between neuromuscular dysfunction and neurobiochemical abnormalities in rats. Tesh. Ross. 84/SHL004/043 from Life Science Research. Wayne. & Dewar. NJ. (1982a). Unpublished report No. T. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) Morrison. USA.. Unpublished report No. Toxicol. (1980). USA. USA.W.E.84. 297-316. B.. D. A. Wayne. (1982b). in-life phase and metabolite profiling (Experiment No. K. 53. NJ. (1988). 2.. (1994). Toxicity of pyrethroid insecticides: Investigation of the neurotoxic potential of WL 43467 to adult domestic hens.P.A. Submitted to the WHO by Cyanamid. USA. Toxicology of pyrethroids: the acute oral and percutaneous toxicity of WL 85871 (cis-2-RIPCORD) comparison with RIPCORD.J. 1105). Sittingbourne Research Centre. (1984a). NJ. WL 43467: Effects of oral administration upon pregnancy in the rabbit.143 from Shell Toxicology Laboratory (Tunstall).J. USA. Submitted to the WHO by Cyanamid. T. SBGR. Unpublished report No.J.. SRCAIR84). & Butterworth. trigeminal nerve and trigeminal ganglion. Pickering.W. NJ.0134. Supplementary report Página 26 de 27 . NJ.B.. USA. F. (1978). Unpublished test report No. NJ. Sittingbourne. Tesh. Unpublished report No. Wayne. SBGR..M. NJ.T. J. G. Submitted to the WHO by Cyanamid. Unpublished report No. Rose. (1984).130 from Shell Research Limited. Unpublished test report No. Comparison with WL43467: The effect of twenty oral doses of WL85871 or WL43467 over a period of 4 weeks on the rat sciatic/posterior tibia nerve.M. Tesh. & Wightman. 84/SHL003/014 from of Life Science Research. Owen. NJ. Sittingbourne Research Centre. R. WL 43467: Effects upon the progress and outcome of pregnancy in the rat. Arch. Unpublished report No. W.82. (1984b). (1981). Wayne. S. Wayne. Toxicology of pyrethroids: the acute oral and percutaneous toxicity of Ripcord (WL-43467). (1983).93.E.M. 6046). Unpublished report from Shell Toxicology Laboratory (Tunstall). (1983). & McAusland. Tesh. Sittingbourne Research Centre. Price. Submitted to the WHO by Cyanamid. Submitted to the WHO by Cyanamid. D.185 from Shell Research Limited. Unpublished report No..77 from Shell Toxicology Laboratory (Tunstall). G.80. 1.299 from Shell Research Limited.. WL85871 (alphacypermethrin. TLGR. S. F.063 from Sittingbourne Research Centre. Submitted to the WHO by Cyanamid. & Richardson.83. Neurotoxicity of WL85871. Main study.P.J. Submitted to the WHO by Cyanamid. Wayne. G.A. WL 43467: Effects of oral administration upon pregnancy in the rabbit.J.
USA. The Netherlands. NJ. USA. 2103). The Netherlands. Unpublished report No. NJ.V.. USA. Página 27 de 27 See Also: Toxicological Abbreviations Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 53) . Wayne. Wayne. SBGR. Submitted to the WHO by Cyanamid. Geneva.J. Sittingbourne Research Centre (Four volumes).J. Switzerland. Vanderwaart. Van der Bercken. Submitted to the WHO by Cyanamid. Cypermethrin and alpha-cypermethrin (WHO Food Additives Series 38) to LSR report No.0188. Studies on the effect of WL 85871 on the integrity of rat liver DNO in vivo (Experiment No. Fourth corrigendum/addendum to TLGR. A 5-week feeding study with WL 85871 in rats (Experiment No. USA. SBGR. Unpublished report No. Submitted to the WHO by Cyanamid.879. (1994). E. Wayne. 087367 from Notox B. (1981). Unpublished report No.78. Vanderwaart. Evaluation of the mutagenic activity of Fastac technical in a in vitro mammalian cell gene mutation test with L5178Y mouse lymphoma cells (with independent repeat). Wooder. The WHO recommended classification of pesticides by hazard and guidelines to classification 1996-1997 (WHO/PCS/96. Available from the International Programme on Chemical Safety.F. Submitted to the WHO by Cyanamid.212 from Shell Research Limited.. (1982). USA.3). Pharmacy and Toxicology. 84/SHL004/043.81. Neurotoxicological effects of pyrethroid insecticides. 2095). NJ. M. NJ. Unpublished report from the Department of Veterinary Pharmacology. Submitted to the WHO by Cyanamid. Sittingbourne Research Centre. Micronucleus test in bone marrow cells of the mouse with Fastac technical.81.P. Submitted to the WHO by Cyanamid. Wayne. (1985). Thorpe. Submitted to the WHO by Cyanamid. J. 88/SHL004/775 from Life Science Research. & Vijverberg. (1989). WHO (1996).225 from Shell Toxicology Laboratory (Tunstall). Unpublished report No. USA. H. NJ. Wayne. NJ. Thorpe. USA. E. E. Wayne. Unpublished report No. Wayne. E.M. University of Utrecht. World Health Organization. The Netherlands. (1995). NJ.V. 087378 from Notox B. Unpublished report from Shell Research Limited.
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