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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

    FENVALERATE

    Explanation

         A temporary ADI was established in 1979 when fenvalerate was
    first evaluated by the JMPR. The 1981 Joint Meeting reviewed
    additional data and requested clarification of the granulomatous
    lesions observed in the mouse and of the giant-cell infiltration seen
    in the rat. The Meetings also desired further information on the
    potential for bioaccumulation and further observations in humans. 1/

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, Distribution, Biotransformation and Excretion

         In support of previous findings, fenvalerate was shown to
    dissipate from the adipose tissue of Sprague-Dawley rats, dosed
    orally with 3 mg/kg of either (2 RS,alpha RS) - or (2S,alpha S) -
    fenvalerate, with a half-life of about seven days in each case. The
    pyrethroid level in the brain of rats treated intraperitoneally with
    2.5 mg/kg (2s,alpha S) - fenvalerate dissipated with a half-life of
    about two days (Marei et al., 1982).

    TOXICOLOGICAL STUDIES

    Special Studies on Microgranulomatous Lesions

         Racemic fenvalerate consists of a mixture of four enantiomers,
    designated A (2S,alpha S), A(2S,alpha R), B alpha(2R,alpha S) and B
    alpha (2R,alpha R), which were employed in the following series of
    experiments. 14C-chlorophenyl-fenvalerate enantiomers, as shown in
    Figure 1, were also utilized.

    FIGURE 1

              

    1/  See Annex 2 for FAO and WHO documentation.

         Studies with single doses of the individual 14C-chlorophenyl
    radiolabelled isomers, orally administered to four male ddy mice at
    2.5 mg/kg, showed almost complete excretion in urine and faeces after
    6 days, predominantly in urine. Analysis of tissue residues, however,
    revealed that the B alpha-isomer gave relatively higher 14C-residues
    in most tissues analyzed, especially adrenals, liver, lymph nodes and
    spleen.

         In a subsequent comparative feeding study, three groups of seven
    to ten male ddy mice were separately maintained on a diet containing
    500 ppm of each of 14C-chlorophenyl-labelled A alpha-, B alpha- and
    B-fenvalerate for one and two weeks. The B alpha- isomer resulted in
    higher 14C levels in all tissues analyzed than the A alpha- and
    B-isomers. Radioactivity concentrations were highest in the adrenals,
    liver and mesenteric lymph nodes. Furthermore, the predominant
    metabolite in these tissues was identified as the ester of (2R)-2-
    (4-chlorophenyl) isovaleric acid and cholesterol (2R)-CPIA-cholesterol
    ester (see Figure 2). Other compounds identified included unchanged B
    alpha- fenvalerate, 2-(4-chlorophenyl)-isovalerate (CPIA) and
    2-(4-chlorophenyl)-3-hydroxymethyl-butenoic acid (3-OH-CPIA). In
    contrast, the tissues of A alpha- and B-treated mice contained
    unchanged parent compound, CPIA and 3-OH-CPIA. CPIA-cholesterol ester
    was not detectable in any tissues of mice treated with the A
    alpha-isomer and was present in only trace amounts in the liver of
    mice treated with the B-isomer.

    FIGURE 2

         (2R)-CPIA-cholesterol ester was also identified in the liver,
    spleen, adrenal and ovary of Charles River SD female rats treated with
    1 500 ppm 14CO-acid-labelled fenvalerate for two weeks. The
    metabolite was identified by co-chromatography with an authentic
    standard (TLC,HPLC,GLC) and the identity confirmed by mass
    spectrometry.

         In a further study, male ddy mice were given a single oral dose
    (70 mg/kg) of 14C-chlorophenyl-B alpha isomer and appropriate tissues
    were analyzed after sacrifice of seven mice within 24 h of treatment.
    CPIA-cholesterol ester was found in intestine, mesenteric lymph nodes,
    blood and kidney, but not in the liver, after 30 minutes. After 1 h,
    it was detected in all tissues analyzed, including the liver and
    spleen.

         The accumulation and elimination of fenvalerate was studied in
    male ddy mice fed racemic 14C-chlorophenyl-fenvalerate at 300 ppm in
    the diet for six weeks and then maintained on basal diet for four
    weeks. Six mice were sacrificed at one, two, four and six weeks during
    treatment and at two and four weeks post-treatment to permit
    determination of 14C-tissue levels. By the sixth week of exposure,
    tissue concentrations of radioactivity had reached a plateau in
    adrenal, liver, fat, spleen and lymph node. The concentrations of
    CPIA-cholesterol ester followed a similar pattern. After cessation of
    dosing, tissue residues of both quickly declined in liver, blood,
    kidney and skin and more slowly in adrenal, lymph node and spleen.

         In a similar study, groups of five male and five female SD-rats
    were fed 14C-chlorophenyl-fenvalerate at 25 ppm in the diet for 35
    days and then maintained on basal diet for a further 84 days. The
    highest concentration of radioactivity accumulated in the following
    decreasing order: fat, adrenal, liver, skin, kidney, spleen, blood,
    testes. The determination of tissue concentrations enabled the
    following half-lives (days) to be estimated: adrenal 84; spleen 33;
    blood 9; fat 9; skin 5; liver 1; and kidney 1.

         The metabolism of the four enantiomers of fenvalerate was also
    studied in vitro using a mouse liver microsomal preparation. The
    B alpha- and B-isomers were hydrolysed more rapidly than the A alpha-
    and A-isomers, suggesting that the rate of enzymatic hydrolysis is
    more dependent on the chirality of the acid rather than the alcohol
    moeity.

         In vitro investigations showed that various mouse tissues
    produced CPIA-cholesterol ester only from B alpha-fenvalerate,
    although a kidney preparation did yield trace amounts from the
    B-isomer. Kidney, liver and brain microsomal fractions proved most
    active in this regard. Free CPIA was not utilized as a substrate.
    Further investigations showed that CPIA was also not a substrate
    for acyl CoA-cholesterol acyl transferase, and that neither
    lecithin-cholesterol acyl transferase nor cholesterol esterase were
    implicated in the synthesis of CPIA-cholesterol ester. However, the
    observation that alkyl alcohols competed with its formation suggests
    that CPIA-cholesterol ester is produced via an ester exchange reaction
    catalyzed by microsomal esterases.

         Additional studies were made in which racemic fenvalerate and the
    four enantiomers were administered to groups of ten male ddy mice in
    the diet for 4, 8, 13, 26, 39 and 52 weeks. Dietary concentrations
    were varied according to the toxicity of the additive, as tabulated in
    Table 1.

        TABLE 1.  Incidence of Fenvalerate-Induced Granulomatous Changes

                                                                                              

    Chemical       Purity        Dosage                    Feeding period (weeks)

                   %             (ppm)        4        8       13       26       39      52
                                                                                              

    A              100.0           500        -        -        0        0        0       0

    A:A           95.2            500        -        -        0        0        0       0
    (1:1)

    Racemate       96.1            500        -        -      100      100      100      95

    B              97.0-99.1       125        0      100      100        -        -       -
                                  1000      100      100      100        -        -       -

    B             99.2-99.7       125        0        0        0        -        -       -
                                  1000        0        0        0        -        -       -

    Control                                   0        0        0        0        0       0
                                                                                              
    
         Typical granulomatous changes occurred in liver, spleen and lymph
    nodes of B alpha-treated groups but not groups treated with the 1:1
    mixture of A alpha and A or the B isomers. The histological
    appearance of microgranulomas and giant-cell infiltrations were
    observed mainly in the medullary cord of lymph nodes, splenic white
    pulp and in the periportal area of the hepatic lobules, but rarely in
    midzonal or centrilobular areas.

         Electron microscopy showed that the ultrastructure of
    granulomatous foci of the B alpha- and racemic-fenvalerate-treated
    groups were similar and that there were many activated macrophages and
    giant-cells in both liver and lymph nodes. There were no remarkable
    changes in the region of the granulomatous cells and little
    lymphocytic involvement or fibrosis. Crystalline rods or needles were
    included within the cytoplasm of macrophages and giant-cells. These
    were also observed in hepatic cells of the B alpha-treated group at 13
    weeks. The liver of mice fed 500 ppm racemic fenvalerate for 52 weeks
    yielded macrophages or giant-cells with a large number of lysosomes
    within the cytoplasm, some of which also contained the cyrstalline
    rods; the latter also occurred within hepatocytes from this group. The

    crystalline inclusions were never observed in the tissues of mice from
    the control group. These studies convincingly demonstrate that the
    B alpha-enantiomer of fenvalerate is causally associated with the
    granulomatous changes observed.

         The identity of the intracellular crystalline rods with
    CPIA-cholesterol ester was subsequently established using male ddy
    mice fed the B alpha- and B-fenvalerate isomers in the diet at
    1 000 ppm for eight and 13 weeks. Tritium-labelled 3H-(2R)-CPIA-
    cholesterol ester was shown to co-locate in hepatic giant and Kupffer
    cells with the previously fed CPIA-cholesterol ester, identified by
    positive staining.

         In a subsequent study in which the (2RS)-, (2R)- and (2S)-CPIA-
    cholesterol esters were administered intravenously to groups of ddy
    male mice, the formation of granulomatous changes was observed after
    seven days. The liver of all treated mice displayed histologically
    identical granulomatous changes, microgranulomas and giant-cell
    infiltrates, such as those in fenvalerate-treated mice. The changes
    were hardly evident in lymph nodes and spleen. The observation that
    all of the enantiomeric esters produced similar changes is
    attributable to the common route of administration.

         In order to elucidate further the fate of the granulomatous
    changes, mice were similarly treated with 10 and 30 mg/kg of the
    (2R)-CPIA cholesterol ester and sacrificed at one, four and eight
    weeks after injection. Micro-granulomatous changes, including
    microgranuloma and giant cell infiltrations, were seen in each case.
    Giant cells were seen clearly at the later stages, whereas
    microgranulomas were more evident at the early stages. The presence of
    the microgranulomas eight weeks after injection is suggestive of
    foreign body microgranulomas.

         To exclude hypersensitivity as the cause of the
    microgranulomatous changes previously observed, groups of five
    BALB/cA/nu/nu/SLC female nude mice were fed dietary racemic
    fenvalerate at 1 000 and 3 000 ppm in the diet for four weeks.
    Histopathological changes typical of the fenvalerate-induced
    microgranuloma were observed in all of the treated mice. This study
    indicates that granulomatous changes induced by fenvalerate are not
    mediated by hypersensitivity reactions (Miyamoto et al., 1984).

         More recently a dose-related incidence of hepatic microgranulomas
    was found in groups of six male and six female beagles fed fenvalerate
    at 0, 250, 500 and 1 000 ppm in the diet for six months. Histiocytic
    cell infiltration of mesenteric lymph nodes also occurred in female
    dogs fed 500 ppm and 1 000 ppm and in males fed 1 000 ppm.
    Multinucleate cells were occasionally seen. The reversibility of these
    effects was not studied (Parker et al., 1984).

    Special Study on Mutagenicity

         Fenvalerate has been shown to be without mutagenicity in
    Salmonella typhimurium strains TA 100 and 98 and in V79 Chinese
    hamster cells, with and without metabolic activation (Pluijmen
    et al., 1984).

    OBSERVATIONS IN HUMANS

         A field study of 16 workers engaged in agricultural application
    of fenvalerate associated exposure with cutaneous symptomatology.
    Paraesthesia usually developed at exposed body sites after some hours
    and the symptoms then progressed from a mild itch to a stinging
    sensation and peaked with numbness. Sweating, exposure to sun or heat
    or the application of water to the exposed site aggravated these
    symptoms. Normal sensation returned with 24 h of cessation of exposure
    (Tucker & Flannigan, 1983).

    COMMENTS

         The data required by the 1981 meeting have been received and
    evaluated. The limited data provided on the tissue distribution of
    fenvalerate confirm the rapid dissipation from fatty tissue,
    indicating a minimal potential of the compound for bioaccumulation.

         A series of elegant studies convincingly demonstrate the
    relationship between th B alpha-isomer of fenvalerate and the
    occurrence of the granulomata in mice, and of giant cell infiltration
    in rats. The mechanism has been demonstrated to be a type of foreign
    body response due to the deposition of crystals of the cholesterol
    2-(4-chlorophenyl)-isovalerate ester in the tissues. Although no 
    dose-response relationship was determined, there is no reason to
    question the previously established no-observable-effect levels in
    rodents.

         A recent study in dogs indicates that similar microgranulomatous
    lesions are formed in this species following fenvalerate
    administration in the diet. There is no reason to doubt that the
    mechanism involved in the formation of these lesions is similar to
    that described for the formation of similar lesions in the rodents.

         Limited mutagenicity studies were negative.

         Observations in humans are limited to field exposure and indicate
    that fenvalerate causes similar cutaneous sensations to those induced
    by other synthetic pyrethroids, possibly as a result of local effects.

    TOXICOLOGICAL EVALUATION

    Level Causing no Toxicological Effect

         Mouse: 30 ppm in the diet, equivalent to 3.5 mg/kg bw

         Rat: 150 ppm in the diet, equivalent to 7.5 mg/kg bw

    Estimate of Temporary Acceptable Daily Intake for Man

         0 - 0.02 mg/kg bw

    FURTHER WORK OR INFORMATION

    Required (by 1986)

    1.   Submission of carcinogenicity studies with fenvalerate
         commissioned by IARC and NTP.

    2.   Determination of the no-effect level in dog with respect to
         granulomata formation and full details of the recently published
         six-month feeding study of fenvalerate in dogs.

    Desirable

    Observations in humans.

    REFERENCES

    Marei A.E. - S.M., Ruzo, L.O. & Casida J.E. Analysis and persistence
    1982      of permethrin, cypermethrin deltamethrin and fenvalerate in
              the fat and brain of treated rats. J. Agric. Food Chem.,
              30: 558-562.

    Parker, C.M. et al. Six-month feeding study of fenvalerate in dogs.
    1984      Fundam. Appl. Toxicol., 4: 577.

    Pluijmen M. et al. Lack of mutagenicity of synthetic pyrethroids in
    1984      Salmonella typhimurium strains and in V79 Chinese hamster
              cells. Mutat. Res., 137: 7-15.

    Tucker, S.B. & Flannigan S.A. Cutaneous effects from occupational
    1983      exposure to fenvalerate. Arch. Toxicol., 54: 195-202.

    Miyamoto, J., Matsuo, M., Okuno, Y. & Kaneko, H. Studies on formation
    1984      of microgranulomatous lesions including giant cell
              infiltration found in mice and rats treated with
              fenvalerate. Laboratory of Biochemistry and Toxicology,
              Takarazuka Research Centre Technical Report AT-40-0370
              submitted by Sumitomo Chemical Co. Ltd., to WHO.
              (Unpublished)


    See Also:
       Toxicological Abbreviations
       Fenvalerate (EHC 95, 1990)
       Fenvalerate (HSG 34, 1989)
       Fenvalerate (Pesticide residues in food: 1979 evaluations)
       Fenvalerate (Pesticide residues in food: 1981 evaluations)
       Fenvalerate (Pesticide residues in food: 1984 evaluations)
       Fenvalerate (UKPID)
       Fenvalerate (IARC Summary & Evaluation, Volume 53, 1991)