PERMETHRIN EXPLANATION Permethrin, a mixture of 4 stereoisomers has been reviewed for acceptable intake by previous JMPR's in 1979, 1981 and 1982 Annex 1, FAO/WHO 1980a, 1982a and 1983a). The 1982 JMPR established an ADI for the 40:60 cis:trans mixture of permethrin stereoisomers only since it recognized that other mixtures of permethrin stereoisomers in different isomeric ratios would require independent evaluation. The present evaluation related to permethrin mixture in which the cis:trans ratio is nominally 25:75. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Toxicological studies Special Study on Carcinogenicity Mice Groups of 75 male and 75 female Anglia CFLP mice received permethrin (25:75) in their diet at 10, 50 and 250 mg/kg/day for 91 weeks. Control groups consisted of 100 animals of each sex. No significant differences in mortality were apparent between the treated and control animals. Body weight gains of treated animals were comparable to controls. The food intake of the high dose female group was decreased in the final ten weeks of treatment only. At necropsy, there were slight but significant increases in liver weight of high-dose males and in renal weight of high-dose females. Lymphoid hyperplasia, malignant lymphoma and reticulum cell sarcoma were frequent in all groups but their incidences were unrelated to treatment. The incidence of pulmonary adenoma was increased in high dose females and reduced in high dose males in comparison to controls. However, these incidences remained within historical control ranges for this strain. Hemangiomas and hemangiosarcomas occurred in the liver and at other sites in each sex, but were not related to treatment. The results of this study do not indicate any carcinogenic potential for permethrin (James et al., 1980). Special Study on Dermal Sensitisation Guinea Pigs Permethrin (25:75) in corn oil (1% w/v) or Freund's complete adjuvant (1% w/v) did not induce dermal sensitisation in groups of 10 male guinea pigs when applied as a 25% dispersion in petrolatum. The positive control, 2,4-dinitrochlorobenzene, (5% w/v) in petrolatum produced marked sensitisation. Thus, permethrin (25:75) did not produce either dermal irritancy or sensitisation under test. conditions (Chesher & Malone, 1974b). Special Study on Teratogenicity Groups of 22-23 female Wistar rats received permethrin (25:75) at 0 or 200 mg/kg in corn oil by daily oral savage on days 6-16 of pregnancy inclusive. Treatment was without apparent effect on maternal bodyweight gain or general condition. The animals were sacrificed on day 20 so that their uterine contents could be examined. Treatment had no effect on the number of corpora lutea, implantations, live fetuses, early and late fetal deaths and fetal abnormalities. Examination of the fetuses, including dissection and skeletal staining, showed no morphological effects of treatment. These results indicate that permethrin (25:75) is not fetotoxic in rats at 200 mg/kg/day (James, 1974). Special Study on Neurotoxicity Rats Groups of 10 male and 10 female Sprague Dawley rats received permethrin (25:75) (94.5% pure) in the diet at 0, 4000, 6000 and 9000 ppm for 21 days. All treated animals developed severe trembling and lost weight. Some of the high-dose rats of each sex died. Subsequent histopathological examination of brain, spinal cord, trigeminal and dorsal root ganglia, proximal and distal root trunks as well as terminal motor and sensory nerves revealed no consistent histopathological abnormality (Dayan, 1980). Special Study on Ocular Irritancy Rabbits Permethrin (25:75) (40% in corn oil) did not produce any ocular effects when instilled (0.1 ml) into the ocular sac of New Zealand rabbits (Chesher & Malone, 1974c). Special Studies on Mutagenicity Mutagenicity study results are presented in Table 1. Special Studies on Reproduction Rats In a 3-generation reproduction study, groups of 20 male and 20 female Wistar COBS rats received permethrin in the diet at 0, 5, 30 and 180 mg/kg/day during growth, mating, gestation, parturition and lactation for 3 generations, each with 2 litters. Fetal toxicity and teratogenicity was assessed in the second pregnancy of the F2 generation Table 1: Special Studies on Mutagenicity Test System Test Organism Concentration Result Reference Ames Test S. typhimurium Permethrin (25:75) Negative Simmon, 1976 ± metabolic TA 1535, TA 1537, 1, 50, 100, 250, activation TA 1538, TA 98, 500, 1000 (ug/plate) TA 100 N-methyl-N-nitro- N-nitrosoguanidine Positive 4-O-tolylazo-O- Positive with toluidine (ug/plate) metabolic activation E. coli WP2 Permethrin (25:75) Negative Simmon, 1976 1, 50, 100, 250, 500, 1000 ug/plate Ames Test S. typhimurium Permethrin (25:75) Negative Clive, 1979 TA 1535, TA 1537, 1.3, 2.5, 5, 10, 20, TA 1538, TA 98, 30, 40, 50 ug/plate TA 100 Mouse Lymphoma L5178Y Permethrin (25:75) Negative Clive, 1977 Assay ± Mouse Lymphoma Cells 0, 31, 47, 62, 94, 125 Metabolic activation (ug/ml) 0, 20, 30, 40, 50 (with activation) ethylmethane sulphonate Positive (620 ug/ml) Table 1: Special Studies on Mutagenicity (cont'd) Test System Test Organism Concentration Result Reference 2-acetylaminofluorene Positive (with activation) (50 ug/ml) dimethyl nitrosamine Positive (75 ug/ml) Dominant Lethal CD-1 mice Permethrin (25:75) Negative Chesher et al., 1975b Assay (452 mg/kg) trimethyl phosphate Positive Treatment with permethrin had no effect on general behaviour, and condition, food intake, bodyweight gain, pregnancy rate of the dams. No effects were seen on parturition, sex ratio or pup weight. A small number of rats of each group developed eye abnormalities, including ocular hemorrage and chronic glaucoma but there was no relationship to treatment. Examination of F3b fetuses showed no treatment-related effect on sex ratio, bodyweight or the occurrence of visceral or skeletal abnormalities. The results of this study indicate that permethrin (25:75) has no effect on the reproduction of rats at doses up to 180 mg/kg/day (James, 1979). Acute Toxicity The acute toxicity of permethrin (25:75) to groups of 6 female C.S.E. Wistar rats was determined in 5 different vehicles as tabulated (Table 2). Most symptoms of acute poisoning developed within 12 hours of dosing and were compromised of muscular tremors, hypersensitivity to stimuli with dullness and staining of abdominal fur. Most deaths occurred between 1 and 3 days (Wallwork & Malone, 1974). Table 2: Acute Toxicity of Permethrin (25:75) to Rats in Different Vehicles Vehicle LD50 (mg/kg) 110% w/v neat undiluted permethrin [control] > 20,090 40% w/v corn oil 4,672 40% w/v petroleum distillate > 8,000 40% w/v dimethyl sulphoxide > 8,000 20% w/v glycerol > 5,048 The influence of diet on acute toxicity was compared in fed and starved rats. Groups of female Sprague-Dawely rats, either fed ad libitum or starved for 24 hours beforehand, received a single oral dose of permethrin (25:75) (94.1% purity) in corn oil solution (40% w/v) at 750, 1500, 3,000 or 6,000 mg/kg. The signs of toxicity were similar in fed and starved rats and included body tremor, hypersensitivity to sound or touch, splayed gait or walking in tip toe and convulsions. Permethrin was more toxic in starved (LD50 3,000 mg/kg) than in fed animals (LD50 4,251 mg/kg) (Piercy et al., 1976). The acute dermal toxicity of permethrin (25:75) applied in xylene (40% w/v) to female Sprague-Dawley rats exceeded 2,000 mg/kg (Harper, et al., 1976). The acute dermal toxicity to male rats similarly exceeded 2,000 mg/kg (Harper et al., 1977). Short term studies Mice Groups of six mature female mice received daily oral doses of permethrin (25:75) corn oil at 0, 200, 400 and 800 and 1600 mg/kg for 10 consecutive days. The animals were sacrificed on the 11th day so that clinical chemical, hematological parameters and organ weights could be recorded. Signs of acute toxicity, namely spasm and convulsion were seen only in the high dose group, half of which died after the initial dose. There were no significant changes observed in hematology, clinical chemistry or body weights. The mice treated at 800 and 1600 mg/kg exhibited increased liver weights (Wallwork et al., 1974a). Rats Groups of 5-6 female Charles River CDI rats received permethrin (25:75) in corn oil at 0, 200, 400 or 800 mg/kg by daily savage for ten days. The animals were sacrificed on the eleventh day so that hematological, clinical chemical parameters and organ weights could be investigated. At 800 mg/kg, signs of toxicity occurred after each dose and 4 rats died. At 400 mg/kg, slight muscle fasciculation and hypersensitivity to stimuli developed only after the initial two doses. Toxicity was not observed at 200 mg/kg. At necropsy, there was a dose-related increase in absolute and relative liver weight and increase in hepatic aspartate amino-transferase, alanine amino-transferase and lactate dehydrogenase activities (Wallwork et al., 1974b). Rabbits Groups of 5 female Dutch rabbits received permethrin (25:75) in ten daily doses by savage in corn oil at 0, 200, 400 or 800 mg/kg. The animals were necropsied on the eleventh day so that clinical chemical, hematological parameters and organ weights could be investigated. One rabbit, dosed at 400 mg/kg, exhibited mild hyperactivity and muscular fasciculation at days six and seven only. Although all animals, including controls, exhibited some degree of weight loss, it was most marked in the high-dose group. There were no significant hematological or clinical chemistry findings but there was some decrease in liver and kidney weight and also some enlargement of adrenal gland weights in all treated groups (Chesher & Malone, 1974a). Dogs Two Beagle dogs received daily oral doses of permethrin (25:75) (500 mg/kg) for 14 days. There were no clinical signs of toxicity or significant effects of treatment on body weight, clinical chemistry or hematological parameters (Chesher et al., 1975a). Groups of 4 male and 4 female beagle dogs received encapsulated permethrin [(25:75) 4.5% w/v] at 0, 10, 50 or 250 mg/kg for 6 months. No signs of toxicity were observed in any group and treatment was without effect on body weight. Ophthalmoscopy and electrocardiography were unremarkable as were routine hematological, clinical chemistry and urinalysis. At necropsy, there were no gross pathological or significant histopathological findings. Hematological and clinical chemistry parameters, including plasma antipyrine elimination rate, were unaffected by treatment. The results of this study indicate that daily oral doses up to 250 mg/kg did not adversely affect the dogs (Reynolds et al., 1978). Long term studies Rats Groups of 60 male and 60 female Wistar SPF rats received 0, 10, 50 or 250 mg/kg bw/day permethrin (25:75) in their diet for 103 consecutive weeks. From week 90 onward a low incidence of generalized body tremor occurred in high-dose rats but survival was reduced in high-dose males only. Body weights and food consumption were not affected by treatment. Ophthalmoscopy and hematological, clinical chemistry and urinalysis parameters remained within normal limits throughout treatment. At necropsy, there was a significant increase in absolute and relative liver weight of high-dose male rats. Histopathology showed a dose-related periacinar hyper-trophy of hepatocytes in mid- and high-dose males only. There were no treatment-related increases in neoplasms. The results of this study do not indicate any oncogenic potential for permethrin and indicate a no-observed effect level of 10 mg/kg/day (McSheehy & Finn, 1980). Observations in humans Two human volunteers, who consumed about 2 and 4 mg of permethrin (25:75), respectively, excreted 18-37% and 32-39% of the administered dose, detected as the metabolite, 3-(2,2-dichlorovinyl)-2,2-dimethyl- cyclopropanecarboxylic acid, after acid hydrolysis of their urine collected over 24 hours (Cridland & Weatherley, 1977a; Cridland & Weatherley, 1977b). In a study to assess the degree of dermal absorption of permethrin from impregnate clothing, a group of 10 male volunteer soldiers wore military clothing for 48 hrs which had been previously treated with an aqueous suspension of permethrin (0.2% w/v). Subsequent analysis showed that the mean concentration of the uniform shirts and trousers was 0.32 g permethrin (25:75)/100 g. However, the average individual exposure to permethrin was 3.8 mg/day. No volunteers complained of irritancy and there were no findings on physical examination (Farquhar et al., 1981a). Two of 17 volunteers developed mild erythema when dermally exposed to permethrin [(25:75) 1% w/w in soft paraffin] for up to 9 days using a patch test (Pegum & Doughty, 1978). To assess the human tolerance, absorption and persistence of permethrin when used as a human pedunculicide (to be used against lice), 10 adult volunteers (4 men, 6 women) were treated with 15-40 ml of permethrin (25:75) (1%) head louse solution. Their hair was allowed to dry naturally and then washed with baby shampoo. Urine samples were collected at 0-24, 24-48. 120-144 and 336-360 hrs to permit estimation of dermal absorption. On assessment, 3 of 10 volunteers developed mild, patchy erythema which faded between days 4-7. Excretion of permethrin in the first 24 hours was only about 1% of the applied dose, whilst the cumulative maximum was only about 5.5 mg over 14 days (Farquhar et al., 1981b). As part of a Stage V evaluation of permethrin (25:75) (5% WDP) in Nigeria, medical surveillance, including urinalysis of staff engaged in bagging, mixing or spraying was undertaken. Medical history, pulse and blood pressure were recorded and urine collected twice daily. This surveillance revealed no effects attributable to permethrin. Despite their use of protective clothing, up to 2 mg of permethrin was excreted within 24 hrs of exposure to up to 6 kg of permethrin (Rishikesh et al., 1978). To assess the safety of permethrin dusts for control of human body lice, approximately 350 people were individually dusted with 50 g of powder containing either 2.5 or 5.0 g/kg of permethrin. Urine samples, taken at the time of treatment and subsequently, indicated that maximal absorption of permethrin was 39 µg/kg, 24 hr after treatment (Nassif et al., 1980). COMMENTS As noted by the 1982 JMPR, the acute toxicity of permethrin (25:75 cis-, trans-) is less than that of permethrin (40:60). On short-term administration to rats and mice, permethrin (25:75) was of similar toxicity to permethrin (40:60). Permethrin (25:75) is not mutagenic in short term tests or in a dominant lethal assay and this isomeric mixture is not carcinogenic in mice or rats. It is also not teratogenic in, and does not adversely affect the reproduction, of rats. Chronic feeding of permethrin (25:75) to rats for 2 years increased the liver weights of male rats, as did permethrin (40:60). The toxicological profile of permethrin (25:75) thus resembles that of permethrin (40:60), although it is less acutely toxic. Accordingly, the meeting agreed to extend the previously established ADI for permethrin (40:60) to include permethrin (25:75). TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT (for the nominal 40% cis-, 60% trans- and 25% cis-, 75% trans- materials) Rat: 100 ppm in the diet, equivalent to 50 mg/kg bw/day ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0-0.05 mg/kg bw. STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED EVALUATION OF THIS COMPOUND Observations in man. REFERENCES Chesher, B.C. & Malone, J.C., 1974a. 10-day cumulative oral toxicity study with 21Z73 in rabbits. Unpublished report from Wellcome Research Laboratories Berkhamsted Doc No. HEFG 74-7. Submitted to WHO by Wellcome Foundation, London, UK. Chesher, B.C. & Malone, J.C., 1974b. Guinea pig sensitisation study with 21Z73 using the maximisation test method. Unpublished report from Wellcome Research Laboratories Berkhamsted Doc No. HEFG 74-3. Submitted to WHO by Wellcome Foundation, London, UK. Chesher, B.C. & Malone, J.C., 1974c. Occular irritancy of 21Z73 in rabbits. Unpublished report from Wellcome Research Laboratories Berkhamsted Doc No. HEFG 74-6. Submitted to WHO by Wellcome Foundation, London, UK. Chesher, B.C., Clampitt, R.C. & Malone, J.C., 1975a. 21Z73 - preliminary investigations into the cumulative oral toxicity on dogs. Unpublished report from Wellcome Research Laboratories Berkhamsted Doc No. HEFG 75-9. Submitted to WHO by Wellcome Foundation, London, UK. Chesher, B.C., Malone, J.C. & Parker, M.J., 1975b. 21Z73, dominant lethal study in male mice. Unpublished report from Wellcome Research Laboratories Berkhamsted Doc No. HEFG 75-10. Submitted to WHO by Wellcome Foundation, London, UK. Clive, C.D., 1977. Mutagenicity of BW21Z73 in L51784/TK± Mouse Lymphoma Cells with and without Exogenous Metabolic Activation. Unpublished report from Burroughs Wellcome Co., Research Triangle Park, N.C. Doc. No. TTEP/77/0011. Submitted to WHO by Wellcome Foundation, London, UK. Clive, C.D., 1979. Mutagenicity Testing of BW0021Z73 in Salmonella. Unpublished report from Burroughs Wellcome Co., Research Triangle Park, N.C. Doc. No. TTEP/79/0034. Submitted to WHO by Wellcome Foundation, London, UK. Cridland, J.S. & Weatherley, B.C., 1977a. Urinary excretion in man of 3-(2,2-dichloro vinyl)-2,2-dimethyl-cyclopropane carboxylic acid ("CVA") after oral ingestion of permethrin (WRDC 143) - A first report. Unpublished report from Wellcome Research Laboratories, Bechenham Doc. No. BDPE 77-1. Submitted to WHO by Wellcome Foundation, London, UK. Cridland, J.S. & Weatherley, B.C., 1977b. An estimate of permethrin (NRDC 143; OMS 1821) absorbed by people employed in a field trial of the insecticide (Kaduna, Nigeria; 7-11 June, 1987). Unpublished report from Wellcome Research Laboratories, Bechenham Doc. No. BDPE 77-3. Submitted to WHO by Wellcome Foundation, London, UK. Dayan, A.D., 1980. 21-Day neuropathological study in the Sprague Dawley rat of Permethrin (21Z73ZJ) administered in the diet. Revised version 2. Unpublished report from Wellcome Group Research and Development, Bechenham Doc. No. BPAT 80/48. Submitted to WHO by Wellcome Foundation Ltd, London, UK. Farquhar, J.A., Hutchinson, D.B.A. Periam, A.W. & Sparkes, R.G., 1981a. An investigation into the absorption of permethrin from impregnated clothing. Wellcome Research and Development Laboratories, Bechenham Doc. No. BKDL/81/1. Submitted to WHO by Wellcome Foundation Ltd (Unpublished). Farquhar, J.A., Hutchinson, D.B.A. Periam, A.W. & Sparkes, R.G., 1981b. An investigation of tolerance to absorption of and persistance of permethrin applied as a 1% lotion to human hair. Wellcome Research and Development Laboratories, Bechenham Doc. No. BKDL/81/2. Submitted to WHO by Wellcome Foundation Ltd (Unpublished). Harper, D.W., Piercy. D.W.T. & James, J.A., 1976. 21Z73 - Dermal toxicity in the female rat. Unpublished report from Wellcome Research Laboratories, Berkhamsted. Doc. No. 77-5. Submitted to WHO by Wellcome Foundation Ltd, London, UK. Harper, D.W., Piercy. D.W.T. & James, J.A., 1977. 21Z73 - Dermal toxicity in the male rat. Unpublished report from Wellcome Research Laboratories, Berkhamsted. Doc. No. HEFG 77-7. Submitted to WHO by Wellcome Foundation Ltd, London, UK. James, J.A., 1974. Fetal Toxicity Study of 21Z73 (NRDC 143) in the rat. Unpublished report from Wellcome Research Laboratories, Bechenham Doc. No. BPAT 74/10. Submitted to WHO by Wellcome Foundation Ltd, London, UK. James, J.A., 1979. A multigeneration reproduction study of 21Z73 (Permethrin) in the rat. Unpublished report from Wellcome Research Laboratories, Bechenham Doc. No. BPAT 79/3. Submitted to WHO by Wellcome Foundation Ltd, London, UK. James, J.A., Taylor, P.E. & Roe, F.J.C., 1980. Carcinogenicity Study in Mice with Permethrin. Unpublished report from Wellcome Research Laboratories, Bechenham Doc. No. HEFG 80-29. Submitted to WHO by Wellcome Foundation Ltd, London, UK. McSheehy, T.W. & Finn, J.P., 1980. 21Z: Potential toxicity and oncogenicity in dietary administration to rats for a period of 104 weeks. Life Science Research Stock Report No. 80/WRL003/283. Unpublished report from Wellcome Research Laboratory Document HEFG 80-33. Submitted to WHO by Wellcome Foundation Ltd, London, UK. Nassif, M., Brooke, J.P., Hutchinson, D.B.A. and Kamel, O.M., 1980. Studies with Permethrin against Bodylice in Egypt. Pesticide Science 11, 679-84. Pegum, J.S. & Doughty, B.J., 1978. Human skin patch test with pyrethrins Kadethrin, permethrin and decamethrin. Wellcome Group Research and Development Berkhamsted Hill Doc. No. NEFJ 78-2. Submitted to WHO by Wellcome Foundation Limited (Unpublished). Piercy, D.W.T., Reynolds, J. & James, J.A., 1976. Effects of diet on the acute toxicity of permethrin in the female rat. Research and Development (V and A) Doc. No. 77-11. Submitted to WHO by Wellcome Foundation Limited (Unpublished). Reynolds, J., Piercy, D.W.T., Clampitt, R.B., James, J.A., Thompson, P.M., Farebrother, D.A. & Dayan, A.D., 1978. Permethrin oral administration to digs for 6 months. Wellcome Research Laboratory Berkhamsted Hill Rep. No. HEFG 78-14. Submitted to WHO by Wellcome Foundation Limited (Unpublished). Rishikish, N., Clarke, J.L., Mathin, H.L., King, J.S. & Pearson, J., 1978. Evaluation of Decamethrins and Permethrin Against Amophiles gambiae and Amopheles funestus in a Village Trial in Nigeria. WHO/VBC/78.679. Simmon, V.F., 1976. In Vitro Microbiological Mutagenicity Study of an FGMC Corporation Compound. Unpublished report from Standford Research Institute Menlo Park, Project LSC-4768. Submitted to WHO by Wellcome Foundation Limited, London, UK. Wallwork, L.M. & Malone, S.C., 1974. 21Z73 (25:75) effect of different solvents on the rat oral toxicity. Unpublished report from Wellcome Research Laboratories, Berkhamsted Doc. No. HEFG 75-4. Submitted to WHO by Wellcome Foundation Limited, London, UK. Wallwork, L.M., Clampitt, R.B. & Malone, J.C., 1974a. 10-day cumulative oral toxicity study with 21Z73 in mice. Unpublished report from Wellcome Research Laboratories, Berkhamsted Doc. No. HEFG 74-9. Submitted to WHO by Wellcome Foundation Limited, London, UK. Wallwork, L.M., Clampitt, R.B. & Malone, J.C., 1974b. 10,-day cumulative oral toxicity study with 21Z73 in rats. Unpublished report from Wellcome Research Laboratories, Berkhamsted Doc. No. HEFG 74-10. Submitted to WHO by Wellcome Foundation Limited, London, UK.
See Also: Toxicological Abbreviations Permethrin (EHC 94, 1990) Permethrin (HSG 33, 1989) Permethrin (ICSC) PERMETHRIN (JECFA Evaluation) Permethrin (Pesticide residues in food: 1979 evaluations) Permethrin (Pesticide residues in food: 1980 evaluations) Permethrin (Pesticide residues in food: 1981 evaluations) Permethrin (Pesticide residues in food: 1982 evaluations) Permethrin (Pesticide residues in food: 1983 evaluations) Permethrin (Pesticide residues in food: 1984 evaluations) Permethrin (JMPR Evaluations 1999 Part II Toxicological) Permethrin (UKPID) Permethrin (IARC Summary & Evaluation, Volume 53, 1991)