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doi: 10.1016/j.aca.2005.02.056

HD1914 with a Cys : Met ratio of 4.0

Toxicological evaluation Levels that cause no toxic effect Mouse: 80 ppm, equivalent to 12 mg/kg bw per day (toxicity in a 78-week study of toxicity and carcinogenicity) Rat: 40 ppm, equivalent to 2 mg/kg bw per day (toxicity in two 2-year studies of toxicity and carcinogenicity) 160 mg/kg bw per day (maternal and developmental toxicity in a study of developmental toxicity) 10 mg/kg bw per day (parental and reproductive toxicity in a two-generation study of reproductive toxicity) Rabbit: 20 mg/kg bw per day (maternal and developmental toxicity in a study of developmental toxicity) Dog: 100 ppm, equivalent to 2.5 mg/kg bw per day (toxicity in a 90-day study of toxicity) Estimate of acceptable daily intake for humans 0-0.02 mg/kg bw Estimate of acute reference dose 0.02 mg/kg bw Studies that would provide information useful for continued evaluation of the compound Further observations in humans Toxicological end-points relevant for setting guidance values for dietary and non-dietary exposure to dimethipin Absorption, distribution, excretion and metabolism in mammals Rate and extent of oral absorption 69% within 24 h, rats Dermal absorption Low dermal penetration, rabbits Distribution Widely distributed, rats Potential for accumulation No evidence of accumulation Rate and extent of excretion 89% within 48 h mainly via urine Metabolism in animals Parent 5000 mg/kg bw Rat, LC 50 , inhalation 0.88 mg/L, 4 h (female) and 1.5 mg/L, 4 h (males) Rabbit, dermal irritation Not irritating Rabbit, ocular irritation Severely irritating Guinea-pig, dermal sensitization Weakly sensitizing Short-term toxicity Target/critical effect Liver: hepatotoxicity, hepatic hypertrophy, rats Lowest relevant oral NOAEL 2 mg/kg bw per day, rats Lowest relevant dermal NOAEL 1000 mg/kg bw per day (highest dose tested), rats Lowest relevant inhalation NOAEL Not determined Long-term toxicity and carcinogenicity Target/critical effect Rat liver: increased weight, liver enzymes, bile-duct hyperplasia

In a cellular model, steatosis was induced in Hep2G cells by exposing them to oleic acid and co-culturing them with vitamin C, N-acetylcysteine, and ASTX

Shirota T, Yamamoto H, Hayashi S, Fujimoto H, Harada Y, Hayashi T