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    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)