TOXICOLOGY
Phosalone was evaluated toxicologically in 1972, when an ADI of 0-0.006 mg/kg bw was established, and re-evaluated in 1975 and 1976. In 1993 an ADI of 0-0.001 mg/kg bw was established on the basis of the lowest dose tested (5 ppm), equal to 0.2 mg/kg bw per day, in a two-year study in rats, with a safety factor of 200 because of concern at the possibly significant occurrence of testicular atrophy and reduction in testicular weight. More information on this study was supplied for consideration at the present Meeting.
Dietary concentrations of 0, 5, 50, or 1000 ppm were used, the highest dose being reduced to 500 ppm later in the study. Significant depression of brain acetylcholinesterase activity was found only at the highest dietary concentration. There was a statistically significant increase in the prevalence of testicular atrophy, a reduction in testicular weights in both the high- and middle-dose groups, and a dose-response relationship across all groups for both effects. All testicular weights were within the historical control range of rats at the institute where the study was performed. The slides were re-examined by a consultant, who argued that the apparent dose-response relationship for testicular atrophy was largely a product of an increase in survival among the rats at the highest dose. Furthermore, it was argued that bilateral atrophy is a more reliable indicator of treatment-related change than unilateral atrophy; on this basis there was no clear dose-response relationship. The findings were also re-examined at the laboratory that originally performed the study; no clear dose-response relationship was found. In view of the fact that neither an earlier long-term study in rats nor studies in mice and dogs gave evidence of changes in the male reproductive system, the Meeting considered the NOAEL to be 50 ppm, equal to 1.8 mg/kg bw per day, on the basis of inhibition of brain acetylcholinesterase activity at the highest dose.
The rat remained the most sensitive species examined, and on the basis of the NOAEL of 1.8 mg/kg bw per day in the above study the Meeting established an ADI of 0-0.02 mg/kg bw, using a safety factor of 100.
An addendum to the toxicological monograph was prepared.
TOXICOLOGICAL EVALUATION
Levels that cause no toxic effect
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Mouse: |
150 ppm, equal to 23 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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Rat: |
50 ppm, equal to 1.8 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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50 ppm, equivalent to 2.5 mg/kg bw per day (multigeneration study of reproductive toxicity) |
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Rabbit: |
10 mg/kg bw per day (study of developmental toxicity) |
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Dog: |
200 ppm, equivalent to 5 mg/kg bw per day (several studies) |
Estimate of acceptable daily intake for humans
0-0.02 mg/kg bw
Studies that would provide information useful for the continued evaluation of the compound
Observations in humans.
