PESTICIDE RESIDUES IN FOOD - 1984 Sponsored jointly by FAO and WHO EVALUATIONS 1984 The monographs Data and recommendations 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 Rome, 24 September - 3 October 1984 Food and Agriculture Organization of the United Nations Rome 1985 PHENOTHRIN Explanation Phenothrin (a 20:80 mixture of the 1 RS-cis and 1 RS-trans isomers) was evaluated by the JMPR in 1979, 1980 and 1982.1 A temporary ADI was estimated in 1980. Studies received by the Joint Meeting in 1982 included mutagenic studies and short-term studies (rat and dog), all of which were performed with "d-phenothrin". The meeting expressed concern about possible differences between the toxicities of 1R- and 1S- isomers and differences between impurities in "d-phenothrin" and phenothrin. Thus, the submitted data were neither summarized nor considered by the 1982 JMPR. The meeting agreed to maintain the original deadline of 1984 for the submission of required data. A comparative metabolism study, information on impurities, an acute intravenous toxicity study and a summary of mutagenicity studies have been considered and are reviewed in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, Distribution, Excretion and Metabolism To elucidate the differences in metabolism between the 1RS- and 1R-isomers of phenothrin, groups of four CD-rats and four ddy mice received a single oral (by gavage) administration of 10 mg/kg bw of either 1R,trans, or 1S,trans, or 1RS,trans, or 1R,cis, or 1S,cis, or 1RS -cis-phenothrin, 14C labelled at the benzyl position of the alcohol moiety. The radiocarbon derived from each isomer was almost completely eliminated from the rat and mouse within six days after administration. Trans isomers were mainly excreted into the urine (rat, 85-88 percent, mice, 65-75 percent) and cis isomers mainly into the faeces (rat, 57-71 percent; mice, 54-71 percent). The amount of 14C in urine and faeces of rats and mice treated with the 1R,cis- and 1R,trans-isomers did not differ significantly from those of the 1RS,cis- and 1RS,trans-isomers respectively. The 1S,cis- and 1S, trans-isomers revealed slightly larger 14C urinary excretion than other 1R, and 1RS,cis- and trans- isomers, respectively. The 14C tissue residues were very low, except in fat. There were no remarkable differences in 14C residue levels among the three trans isomers and the three cis isomers. The 14C levels of the cis isomers in fat (maximum 3.5 ppm) were three to seven times higher than those of the trans isomers (less than 1 ppm). 1/ See Annex 2 for FAO and WHO documentation. The major urinary and faecal metabolites were remarkably similar in both rats and mice, although N-3-phenoxybenzoyl taurine was characteristic in mice. In both rats and mice there were virtually no differences in the metabolic fate of the 1R,trans- and 1RS,trans- isomers or of the 1R,cis- and 1RS,cis-isomers (Izumi et al., 1984). TOXICOLOGICAL STUDIES Special Studies on Impurities of Phenothrin and d-Phenothrin Phenothrin is manufactured by esterification of 3-phenoxybenzyl alcohol with 1RS-cis, trans-chrysanthemate, whereas "d-phenothrin" is produced by using 1R-cis, trans-chrysanthemate as the acid moiety. The purity of the chrysanthemate esters and the contents of impurities in several representative commercial products are shown in Table 1. As shown in the table, there are no major differences between phenothrin and d-phenothrin in the contents of impurities, which are mainly derived from either acid or alcohol moieties (Miyamoto et al., 1984). Special Studies on Mutagenicity A summary of results obtained in several bacterial test systems is shown in Table 2. Neither phenothrin nor d-phenothrin was found to be mutagenic, even at the maximum concentrations which are technically feasible. The 1S-isomers would be expected to yield the same results if under similar test conditions (Miyamoto et al., 1984). Acute Toxicity The acute toxicities of phenothrin (1RS-isomers; cis-trans ratio approximately 20:80) and d-phenothrin (1R-isomers; cis-trans ratio approximately 20:80) are virtually identical in male and female rats and mice (see Table 3). Table 4 compares 1R and 1RS isomers by intravenous injection to mice (Hiromori et al., 1984). COMMENTS Phenothrin (a 20:80 racemic mixture of (1RS), cis- and (1RS), trans-isomers) was evaluated in 1979 and 1980 and a temporary ADI was estimated in 1980. No differences between phenothrin and "d-phenothrin" (a mixture of predominantly (1R), cis- and (1R), trans- isomers, with a cis:trans ratio of 20:80) were found in the acute oral toxicity test. There is no substantial difference between phenothrin and d-phenothrin in the content of impurities. Phenothrin and d-phenothrin were negative in several mutagenicity studies. TABLE 1. Analytical Results of Several Phenothrin and d-Phenothrin Products Percent by weight 3-Phenoxy- 3-Phenoxy- 4-Phenoxy- 3-Phenoxy-6- Hydro- (3) benzyl cis, C-(2) Ethyl 3-Phenoxy- benzyl benzyl cis, Br-benzyl cis, carbon Lot No. trans-CA(1) acid CA toluene alcohol trans-CA trans-CA solvent Phenothrin T-3 94.1 0.02 2.0 0.5 0.2 0.6 0.7 0.2 T-4 93.4 0.02 2.0 0.5 0.1 0.5 0.6 0.3 T-5 92.0 0.01 1.8 0.6 0.4 0.9 0.8 0.2 T-6 92.5 0.1 2.2 0.7 0.2 0.8 1.2 0.1 T-7 92.9 0.1 2.3 0.8 0.1 0.8 1.4 0.1 Average 93.0 0.1 2.1 0.6 0.2 0.7 0.9 0.2 d-Phenothrin 11129 93.4 0.04 2.40 0.50 0.30 0.50 0.60 0.30 11231 92.3 0.02 2.30 0.50 0.30 0.80 0.60 0.30 20301 94.5 0.04 2.27 0.43 0.28 0.31 0.80 0.06 20303 94.8 0.02 2.30 0.40 0.20 0.30 0.70 0.06 20305 94.5 0.04 2.00 0.40 0.10 0.30 0.60 0.09 20309 93.3 0.03 2.50 0.40 0.10 0.20 0.70 0.30 20315 94.8 0.04 2.40 0.40 0.20 0.30 0.60 0.10 Average 94.0 0.04 2.31 0.43 0.27 0.39 0.66 0.18 (1) CA: Chrysanthemate (2) C-acid: Chrysanthemic acid (3) Hydrocarbon solvent: mainly toluene TABLE 2 Results of Mutagenicity Studies on Phenothrin and d-Phenothrin Phenothrin d-Phenothrin Test Strain Dose Result Strain Dose Result (Animal) (Animal) Repair B. subtilis ug/disc B. subtilis ug/disc Test M45 (rec-) 20 M45 (rec-) 10 H17 (wild) 100 H17 (wild) 50 200 100 500 Negative 500 Negative 1 000 1 000 2 000 5 000 10 000 Reversion S. typhimurium ug/plate S. typhimurium ug/plate Test -- TA1535 10 TA1535 10 TA1537 50 TA1537 50 TA1538 100 Negative TA1538 100 Negative TA98 500 TA98 500 TA100 1 000 TA100 1 000 E. coli (with & without E. coli 5 000 WP2hcr S9 mix) WP2uvrA (with & without 3 000 S9 mix) (without S9 mix) Host- S. typhimurium S. typhimurium mediated G46 G46 Test mg/kg mg/kg ICR mouse 500x2 Negative ICR mouse 2 500x2 Negative male (p.o.) 1 500x2 male (p.o.) 5 000x2 TABLE 3. Acute Toxicity of Phenothrin and d-Phenothrin in Rats and Mice LD50 (mg/kg) Routes Rats Mice Male Female Male Female Phenothrin Oral >5 000 >5 000 >5 000 >5 000 Subcutaneous >5 000 >5 000 >5 000 >5 000 Dermal >5 000 >5 000 >5 000 >5 000 Intraperitoneal >5 000 >5 000 >5 000 >5 000 Inhalation 1 >1 210 >1 210 >1 210 >1 210 d-Pehnothrin Oral >10 000 >10 000 >10 000 >10 000 Subcutaneous >10 000 >10 000 >10 000 >10 000 Dermal >10 000 >10 000 > 5 000 > 5 000 Intraperitoneal >10 000 >10 000 >10 000 >10 0002 Inhalation 1 > 1 180 > 1 180 > 1 180 > 1 180 1 LC50 value: mg/m3 2 Mortality at 10 000 mg/kg was 12.5 percent. TABLE 4 Acute Intravenous Toxicity of Phenothrin and d-Phenothrin in Mice LD50 (mg/kg) Compound Male Female Phenothrin 470 600 d-Phenothrin 265 315 Data presented indicate the similarity in metabolism and toxicity of phenothrin and d-phenothrin, thus indicating that data for phenothrin can be used to support the toxicological data base for d-phenothrin. Six-month studies performed in both rats and dogs using d-phenothrin demonstrated the absence of adverse effects at 1 000 and 300 ppm, respectively. Information was provided indicating that ongoing rodent reproduction, chronic toxicity and oncogenicity studies with d-phenothrin would be completed in 1985 and 1986 to replace previously identified studies from Industrial Bio-Test Laboratories. The meeting therefore allocated a temporary ADI for d-phenothrin based on the six-month rat and dog studies until these further data are submitted. TOXICOLOGICAL EVALUATION Level Causing no Toxicological Effect Rat: 1 000 ppm in the diet, equivalent to 50 mg/kg bw Dog: 300 ppm in the diet, equivalent to 7.5 mg/kg bw Estimate of Temporary Acceptable Daily Intake for Man 0 - 0.04 mg/kg bw FURTHER WORK OR INFORMATION Required (by 1988) 1. Submission of the on-going long-term studies in rats and mice. 2. Submission of the on-going reproduction study in rat. Desirable Observations in humans. REFERENCES Izumi, T., Kaneko, H., Matsuo, M & Miyamoto, J. Comparative metabolism 1984 of the six optical stereo isomers of Phenothrin in rats and mice. J. Pesticide Sci. (in press). Submitted by Sumitomo, Japan, to WHO. Hirmori T, Hara, S., Kadota, T. & Miyamoto, J. Acute intravenous 1984 toxicity of phenothrin and d-phenothrin in mice. Report from Takarazuka Research Center, submitted by Sumitomo, Japan, to WHO. (Unpublished) Miyamoto, J., Kogiso, S. & Matsuo, M. Additional toxicological 1984 information for phenothrin. Report No. ET-40-0090 from Takarazuka Research Center submitted by Sumitomo, Japan, to WHO. (Unpublished)
See Also: Toxicological Abbreviations Phenothrin (Pesticide residues in food: 1979 evaluations) Phenothrin (Pesticide residues in food: 1980 evaluations)