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)