VINCLOZOLIN
EXPLANATION
Vinclozolin was reviewed by the JMPR in 1986 (FAO/WHO 1987a) and
a Temporary ADI of 0-0.04 mg/kg bw was estimated. "Metabolite T" was
identified as a major plant metabolite which had not been fully
evaluated with respect to toxicity. Additional testing of metabolite T
was determined necessary before an ADI could be allocated. These data
have been submitted and are reviewed in this monograph addendum.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Toxicological Studies
Acute toxicity
Rats
Metabolite T (3,5-dichlorophenylcarbamoyl-2-propionic acid)
(purity >98%) was administered via oral savage in aqueous
carboxymethyl cellulose to Wistar rats. Single oral doses of 1000,
1780, 2610 and 3830 mg/kg bw were given to 5 male and 5 female rats
per dose group. Each group was observed for 14 days. An LD50 =
2740 mg/kg bw in males. The significance of cageside observations
increased with doses of 1780 mg/kg bw and included the following:
dyspnea, abnormal position, staggering, atonia, paresis, piloerection
and poor general state (Kirsch, 1986a).
Mice
In an identical protocol to the rat acute study, NMRI mice were
orally gavaged with metabolite T at doses of 500, 1000 and 2000 mg/kg
bw. There were 5 male and 5 female mice per dose group. The LD50 was
greater than 2000 mg/kg bw. Cageside observations included: dyspnea,
staggering, piloerection and poor general state (Kirsch, 1986b).
Special studies on mutagenicity
Metabolite T was negative in a number of acceptable mutagenicity
studies, which included assessments of gene mutations and chromosomal
aberration. Summary results are presented in Table 1.
COMMENTS
"Metabolite T", 3,5-dichlorophenylcarbamoyl-2-propionic acid, was
evaluated for acute toxicity in rats and mice, and for mutagenic
activity in the Ames test, Rec assay and an in vitro cytogenetic
assay in Chinese hamster ovary cells. These studies indicate that
metabolite T is not mutagenic in the test systems analyzed. Although
the acute oral toxicity studies demonstrate that metabolite T is more
acutely toxic to rats and mice than vinclozolin, the 1986 Residue
Evaluations indicate that it is a transient residue (also found in
conjugated form) in only two commodities and is therefore not a
residue of concern. The Meeting therefore estimated an ADI for
vinclozolin.
Table 1. Results of mutagenicity studies on "Metabolite T"
Test system Test object Concentration of Purity Results Reference
Vinclozolin (%)
Ames assay 1/ S. typhimurium 0, 20, 100, 500, >98 Negative Gelbke, 1986
TA-98, 100, 2500, 5000 µg/plate 2/
TA-1535, 1537
Rec assay 1/ Bacillus 0, 10, 100, 500, >98 Negative Hoorn, 1987
subtills 1000, 2500, 5000, 2/
strains H17 10000 µg/plate
CHO/HGPRT 1/ Chinese 5-500 µg/ml, and >98 Negative Taalman, 1986
Chromosome hamster 250-1500 µg/ml 2/
aberration ovary cells
1/ With and without activation.
2/ The positive controls gave the expected positive response.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Mouse: 486 ppm in the diet, equal to 86.8 mg/kg bw/day
Rat: 486 ppm in the diet, equal to 27.2 mg/kg bw/day
Dog: 100 ppm in the diet, equal to 7.19 mg/kg bw/day
ESTIMATE FOR ACCEPTABLE DAILY INTAKE FOR MAN
0-0.07 mg/kg bw
REFERENCES
Gelbke, P. 1986. Report on the study of Vinclozolin - Metabolite "T"
BF 352-42 in the Ames test. Report No. 861398. Submitted to WHO by
BASF Aktiengesellschaft, Ludwigshafen/ Rhein FRG.
Hoorn, A. 1987. Report on the mutagenic evaluation of Winclozolin
Metabolite "T" in the Rec assay with Bacillus subtilis. Report
No. 87/028. Submitted to WHO by BASF Aktiengesellschaft,
Ludwigshafen/Rhein FRG.
Kirsch, P. 1986a. Report on the study of the acute oral toxicity
on the rat based on OECD and EPA (FIFRA) of Vinclozolin Metabolite
BF 352-42. Report No. 86/402. Submitted to WHO by BASF
Aktiengesellschaft, Ludwigshafen/Rhein FRG.
Kirsch, P. 1986b. Report on the study of the acute oral toxicity on
the mouse based on OECD and EPA (FIFRA) of Vinclozolin Metabolite
BF 352-42. Report No. 86/403. Submitted to WHO by BASF
Aktiengesellschaft, Ludwigshafen/Rhein FRG.
Taalman, R. 1986. Report on the clastogenic evaluation of Vinclozolin
Metabolite "T" on an in vitro cytogenetic assay measuring chromosome
aberration frequency in Chinese hamster ovary (CHO) cells. Report
No. 86/418. Submitted to WHO by BASF Aktiengesellschaft,
Ludwisshafen/Rhein FRG.