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)