AGP:1970/M/12/1 WHO/FOOD ADD/71.42 1970 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD THE MONOGRAPHS Issued jointly by FAO and WHO The content of this document is the result of the deliberations of the Joint Meeting of the FAO Working Party of Experts and the WHO Expert Group on Pesticide Residues, which met in Rome, 9-16 November, 1970. FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS WORLD HEALTH ORGANIZATION Rome, 1971 PYRETHRINS Explanation This insecticide was considered at joint Meetings held in 1966, 1967, 1968 and 1969. In 1969 (FAO/WHO 1970b), the only data considered related to use, together with piperonyl butoxide, on fish. This 1970 meeting confined itself to a consideration of data relating to the evaluation of the acceptable daily intake. This consideration is summarized in the following addendum. IDENTITY In this addendum, the term pyrethrins refers to the mixed active ingredients as present in commercially available extracts of pyrethrum. Such extracts contain about 30 percent by weight a mixture of six components in about the following amounts: pyrethrin I (11.4 percent), cinerin I (2.2 percent), jasmolin I (1.2 percent), pyrethrin II (10.5 percent), cinerin II (3.5 percent) and jasmolin II (1.2 percent) (Head, 1969). EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Biotransformation Utilizing an in vitro enzyme system from insects in the presence of NADPH2, Yamamoto and Casida (1966) showed that pyrethrin I was converted to at least ten metabolites. A major metabolite was characterized as a product which had undergone oxidation of a methyl group in the isobutenyl moiety to the carboxylic acid. In a more comprehensive study, these authors conclude that oxidation rather than hydrolysis in insects might be the major mode of metabolism of pyrethroid chemicals (Yamamoto et al., 1969). Pyrethrins I and II have been shown to be oxidatively metabolized in rats. Oxidation was found to occur at the trans-methyl group of pyrethrin I as well as on the pentadienyl side chain to produce two diols. These metabolites were also found in conjugate form (Casida et al., 1970). TOXICOLOGICAL STUDIES Special studies on reproduction Rabbit Two groups of nine rabbits each were administered pyrethrins at 0 and 90 mg/kg body-weight/day, orally, from day 8-16 of gestation. Pups were delivered by normal parturition or by caesarian section on day 30 of gestation. No apparent effects were noted on the number and weight of foetuses, implantation sites or on gross external and internal examination. Two control pups and one pup in the group given pyrethrins had a club-like deformed front paw, and one pyrethrin pup had a missing caudal vertebrae. There appears to be no apparent teratogenic effects elicited by pyrethrins in rabbits (Weir, 1966a). Special studios on skin sensitization Guinea pig Two groups of nine male guinea pigs were used to examine the sensitizing effect of pyrethrins. The criterion of sensitization was a comparison of the response following a challenge dose with the response elicited by previous sensitizing doses. A positive control (1-chloro-2,4-dinitrobenzene) produced sensitization in all animals of one group. No sensitization was obtained with a 1 percent formulation of pyrethrins (Weir, 1966b). Acute toxicity LD50 (mg/kg Species Route body-weight) Reference Rat (M) oral 710 Weir 1966c Rat oral 584-900 Malone & Brown, 1968 i.p. 167-798 Malone & Brown, 1968 Mouse oral 273-796 Malone & Brown, 1968 i.p. 172-452 Malone & Brown, 1968 Chick Perivisceral 240-1262 Malone & Brown, 1968 The latter five ranges comprise various grades of pyrethrum, including crude oleoresins and refined concentrates. The acute signs of poisoning in rats include: depression, rapid and/or laboured respiration, ataxia, incoordination, convulsions and muscular tremors. Necropsy findings include: congestion of the lungs, liver, kidneys, adrenals and pancreas and slight gastric inflammation (Weir, 1966c; Malone and Brown, 1968). An acute dermal toxicity test was performed with rabbits using pyrethrins in combination with a synergist. Typical sprays made with the synergists, tropital or piperonyl butoxide (1 percent) in combination with 0.1 percent pyrethrins, exhibited a low order of toxicity when tested dermally on 6-12 male rabbits. The acute dermal LD50 of both formulations was >10 gm/kg. At 10 gm/kg with tropital, three of 12 rabbits died. At 5 and 10 gm/kg, body-weight gain was reduced and transient signs of toxicity were evident with both synergist combinations. No effects were noted at a concentration of 2 gm/kg (equivalent to 2 mg/kg pyrethrins and 20 mg/kg synergist) (Wisconsin, 1965) Short-term studies Rat Two groups of rats (ten male and ten female) were exposed to aerosols of 1 percent pyrethrins for one hour. The flow was 50 l/min containing 2 mg/l of air. Gross examination of the lung tissue demonstrated the presence of haemorrhagic pin point lesions in nine of ten male and ten of ten female rats exposed to pyrethrins (Leong and Martin, 1966). Microscopic examination of the lungs indicated that the alterations were typical of those found in murine pneumonitis (Weir and Crews, 1966). No distinguishing pathological observations were reported which might be attributed to pyrethrins. Rabbit A group of rabbits (ten male and ten female) and a control group (five male and five female) were tested by repeated dermal application to either abraded or intact skin with a 1.0 percent formulation of pyrethrins at doses of 0 and 10 mg/kg body-weight/day. Treatments of 1 ml/kg body-weight of the formulation were applied daily (6-8 hour exposure per day) five days per week for three weeks. No systemic, clinical or necrotic findings were attributed to the test material. Repeated dermal applications of a 1 percent formulation of pyrethrins was not detrimental to rabbits (Weir, 1966d). Long-term studies No new information available. OBSERVATIONS IN MAN Two hundred human subjects (177 females, 23 males) were patch tested for skin sensitivity and irritation using pyrethrins at 1 percent in water simulating formulation levels. Under the conditions of this patch test, pyrethrins at the 1 percent formulation level was not a primary irritant and was not a sensitizer to human skin (Weir, 1966e). COMMENT Skin sensitization studies using very low levels of pyrethrins have been negative. Dermal and inhalation toxicity studies of pyrethrins in combination with synergists, using a commercial formulation, exhibited a low order of toxicity to rabbits. Further studies of this type, using especially the methylenedioxy synergists would, however, appear desirable. A rabbit reproduction study indicated that pyrethrins were not teratogenic. Some limited information on the mammalian metabolism of pyrethrins has recently become available. The short-term studies in the dog and other species requested at the 1966 Joint Meeting with a view to elucidating the effect on the liver found in a long-term study in rats, have not been forthcoming. The Committee therefore decided to retain the acceptable daily intake on a temporary basis. TOXICOLOGICAL EVALUATION Level causing no toxicological effect Rat: 200 ppm in the diet, equivalent to 10 mg/kg body-weight/day ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN 0-0.04 mg/kg body-weight FURTHER WORK OR INFORMATION REQUIRED (before June 1973) Short-term toxicity studies in several species including a non-rodent mammalian species, with special emphasis on the effects on the liver and a detailed study of the mammalian metabolism of pyrethrins. DESIRABLE Further studies to determine if mammalian toxicity to pyrethrins is increased when they are used along with synergists, especially with methylenedioxy compounds such as piperonyl butoxide. REFERENCES Casida, J.E., Kimmel, E.C., Elliot, M. and Janes, N.F. (1970) Oxidative metabolism of pyrethrins in mammals. Unpublished report submitted to WHO FAO/WHO. (1967) Evaluation of some pesticide residues in food. FAO. PL:CP/15; WHO/Food Additives/67.32 Head, S.W. (1969) The composition of pyrethrum extract. Pyrethrum Post, 10: 1-5 Leong, K.J. and Martin, A.R. (1966) Acute inhalation exposures - Rats. o/w Emulsion of neopynamin, o/w emulsion of pyrethrin. Unpublished report from Hazelton Laboratories, Inc. (31 March 1966) to S.C. Johnson and Son, Inc. Malone, J.C. and Brown, N.C. (1968) Toxicity of various grades of pyrethrum to laboratory animals. Pyrethrum Post, 9: 3-8 Weir, R.J. (1966a) Reproduction study - rabbits. Neopynamin and pyrethrin. Unpublished report (3 August 1966) from Hazelton Laboratories, Inc. to S.C. Johnson and Son, Inc. Weir, R.J. (1966b) Skin sensitization study - guinea pigs. Neopynamin and pyrethrin. Unpublished report (1 June 1966) from Hazelton Laboratories, Inc. to S.C. Johnson and Son, Inc. Weir, R.J. (1966c) Acute potentiation study - oral administration, rats. Neopynamin and pyrethrin. Unpublished report from Hazelton Laboratories, Inc. (1 June 1966) to S.C. Johnson and Son, Inc. Weir, R.J. (1966d) Repeated dermal application - rabbits. Neopynamin and pyrethrin. Unpublished report from Hazelton Laboratories, Inc. (1 June 1966) to S.C. Johnson and Son, Inc. Weir, R.J. (1966) Human patch test. Unpublished report (3 November 1966) from Hazelton Laboratories, Inc. to S.C. Johnson and Son, Inc. Weir, R.J. and Crews, L.M. (1966) Supplement to acute inhalation exposures - rats. Unpublished report from Hazelton Laboratories, Inc. (1 June 1966) Wisconsin. (1965) Unpublished report (23 September 1965) from the Wisconsin Alumni Research Foundation Yamamoto, I. and Casida, J.E. (1966) 0-demethylpyrethrin II analogs from oxidation of pyrethrin I, allethrin dimethrin and phthalthrin by a house fly enzyme system. J. econ. Entomol., 59: 1542-1543 Yamamoto, I., Kimmell, E.C. and Casida, J.E. (1969) Oxidative metabolism of pyrethroids in houseflies. J. Agr. Fd. Chem., 17: 1227-1236
See Also: Toxicological Abbreviations Pyrethrins (FAO Meeting Report PL/1965/10/1) Pyrethrins (FAO/PL:CP/15) Pyrethrins (JMPR Evaluations 2003 Part II Toxicological) Pyrethrins (FAO/PL:1967/M/11/1) Pyrethrins (FAO/PL:1968/M/9/1) Pyrethrins (FAO/PL:1969/M/17/1) Pyrethrins (WHO Pesticide Residues Series 2) Pyrethrins (WHO Pesticide Residues Series 4)