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    CARBOSULFAN

    EXPLANATION

         Carbosulfan was evaluated for acceptable daily intake by the Joint
    Meeting of 1984 (Annex 1, FAO/WHO, 1985b), at which time a temporary
    acceptable daily intake (Temporary ADI) of 0-0.005 mg/kg b.w. was
    allocated. A toxicology monograph was prepared (Annex 1, FAO/WHO,
    1985c). Additional information was required to clarify the different
    pathological interpretations of the ophthalmological data in a 2-year
    mouse study in order to determine a NOEL for the cataract effects. An
    independent ophthalmologic examination has been provided and is
    considered in this monograph addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Toxicological study

    Special study on cataractogenesis

    Mice

         Evaluation of the 24-month carcinogenicity study in CD-1 mice
    (DeProspo et al., 1982) identified an apparent difference of opinion
    expressed by two separate ophthalmologists regarding the incidence of
    cataracts observed in male mice. Table 1 summarizes their findings.

    Table 1. Incidence of cataracts observed intraocularly in male mice.
                                                                        

                              FMC1                            IRDC2
                                                                       
        Group          N     Cataracts (%)           N       Cataracts (%)
                                                                        

    Control            46       6 (13)              44         33 (75)

    10 ppm             34       6 (18)              32         27 (84)

    20 ppm             42       7 (17)              39         39 (100)

    500 ppm            46      12 (26)              42         39 (93)

    2500 ppm           34      10 (29)              33         33 (100)
                                                                        

    1  Examined in week 102
    2  Examined in week 105

         An independent evaluation by Dr L.F. Rubin, Professor of
    Ophthalmology at the University of Pennsylvania School of Veterinary
    Medicine, has been provided, which indicates that in his opinion the
    apparent differences are the result of different criteria used by the
    original two examiners to define the lesion. The criteria utilized by
    the International Research and Development Corporation examiner quite
    possibly considered local senescent refractive changes to be the
    equivalent of cataracts, while the FMC Corporation examiner considered

    these changes to be those normally associated with aging. Cataracts
    are nonreversible lesions which can be observed histologically as dead
    lenticular fibers, but this was not evident in the histologic sections
    reported below in Table 2, and therefore no evidence for catarac-
    togenesis was demonstrated in this study (Letters of 11 December 1985
    from L.F. Rubin to J.R. DeProspo concerning cataracts in IRDC Study
    No. 167-147 [24-month oncogenicity study in mice]. Submitted to WHO
    by FMC Corporation, Princeton, NJ, USA.)

    Table 2.  Incidence of cataracts observed histologically in male mice.
                                                                        

                              FMC1                            IRDC2
                                                                        
       Group           N     Cataracts (%)          N       Cataracts (%)
                                                                        

    Control            46       30 (65)             44        30 (68)

    10 ppm             34        9 (26)             32         9 (28)

    20 ppm             42        8 (19)             39         8 (21)

    500 ppm            46       18 (39)             42        18 (43)

    2500 ppm           34       19 (56)             33        18 (55)
                                                                        

    1   Represents the incidence observed histologically in those animals
        examined ophthalmologically.

    COMMENTS

         The concern expressed for the cataractogenic potential of
    carbosulfan in mice has been alleviated with the submission of
    additional expert opinion and clarification. The NOEL of 10 ppm in the
    mouse carcinogenicity study has been reaffirmed. This enabled the
    Meeting to convert the temporary ADI to an ADI at a higher level.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT:

         Mice:     10 ppm in the diet, equal to 1.3 mg/kg b.w./day.
         Rats:     20 ppm in the diet, equal to 1.0 mg/kg b.w./day.
         Dogs:     50 ppm in the diet, equivalent to 1.25 mg/kg b.w./day.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN:

         0 - 0.01 mg/kg b.w.

    FURTHER WORK OR INFORMATION

    STUDIES WHICH WILL PROVIDE INFORMATION FOR THE CONTINUED EVALUATION OF
    THE COMPOUND

         Observations in man.

    REFERENCE

    DeProspo, J.R., Norvell, M.J., & Fletcher, M.J., 1982. Twenty-four
         month dietary toxicity/oncogenicity study in mice with FMC 35001.
         Unpublished report No. A79-334 from FMC Corporate Toxicology
         Department. Submitted to WHO by FMC Corporation, Princeton,
         NJ, USA.
    


    See Also:
       Toxicological Abbreviations
       Carbosulfan (JMPR Evaluations 2003 Part II Toxicological)
       Carbosulfan (Pesticide residues in food: 1984 evaluations)
       Carbosulfan (Pesticide residues in food: 1984 evaluations)