Risk assessment report
Folpet (Pesticides)
Summary
2017 Volume 5 Issue 2 Pages 67-71
Details
2017 Volume 5 Issue 2 Pages 67-71
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of folpet (CAS No. 133-07-3), a phthalimide fungicide, based on results from various studies. Major adverse effects of folpet were observed in hyper-keratosis in rats and in duodenal mucosal hyperplasia in mice. No neurotoxicity and adverse effect on fertility were detected. Increases in the incidence of duodenal adenoma and adenocarcinoma were identified in carcinogenicity studies in mice. FSCJ recognized no genotoxicity relevant to human health of folpet in spite of the positive results in vitro. Therefore, a genotoxic mechanism was unlikely involved in the tumor development, and it enabled us to establish a threshold in the assessment. In developmental toxicity studies, no adverse effects observed in fetus at the dose without maternal toxicity. No folpet-induced teratogenicity was detected in rats. Folpet (parent compound only) was identified as the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all the studies was 10 mg/kg bw/day in several studies in dogs, rats and rabbits. FSCJ specified an acceptable daily intake (ADI) of 0.1 mg/kg bw/day by applying a safety factor of 100 to the NOAEL. The lowest NOAEL for potential adverse effects of a single oral administration of folpet was 10 mg/kg bw/day in a developmental toxicity study in rabbits. FSCJ specified an acute reference dose (ARfD) of 0.1 mg/kg bw/day, for women who are or may be pregnant, by applying a safety factor of 100 to the NOAEL. FSCJ considered it unnecessary to specify ARfD for general population.
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of folpet (CAS No. 133-07-3), a phthalimide fungicide, based on results from various studies.
The data used in the assessment include fate in animals (rats, mice and goats), fate in plants (tomatoes and grapes), subacute toxicity (rats and dogs), subacute neurotoxicity (rats), chronic toxicity (rats and dogs), combined chronic toxicity/carcinogenicity (rats), carcinogenicity (rats and mice), two-generation reproductive toxicity (rats), developmental toxicity (rats and rabbits) and genotoxicity, and also mechanism studies related with tumor development of duodenum in mice.
Major adverse effects of folpet were observed in hyperkeratosis in rats and in duodenal mucosal hyperplasia in mice. No neurotoxicity and adverse effect on fertility were detected.
Increases in the incidence of duodenal adenoma and adenocarcinoma were identified in carcinogenicity studies in mice. FSCJ comprehensively evaluated a number of genotoxicity studies in vitro and in vivo, and mechanism studies. Negative results were obtained from in vivo studies, including a comet study in the duodenum of mice treated with the high doses (up to four-times excess of the carcinogenicity study). FSCJ, thus, recognized no genotoxicity relevant to human health of folpet in spite of the positive results in vitro. Therefore, a genotoxic mechanism was unlikely involved in the tumor development, and it enabled us to establish a threshold in the assessment.
In developmental toxicity studies, folpet, at the dose causing maternal toxicity, increased incidences of hydrocephalus (lateral ventricular enlargement) and abnormality of the stomach in the rabbit fetus. No adverse effects observed in fetus at the dose without maternal toxicity. No folpet-induced teratogenicity was detected in rats.
Based on the results from studies available, folpet (parent compound only) was identified as the residue definition for dietary risk assessment in agricultural products.
The lowest no-observed-adverse-effect level (NOAEL) obtained from all the studies was 10 mg/kg bw/day based on the adverse effects in a one-year chronic toxicity study in dogs (the 2nd study in Table 1), a developmental toxicity study in rats (the 1st study in Table 1) and developmental toxicity studies in rabbits (the 1st and 2nd studies in Table 1). FSCJ specified an acceptable daily intake (ADI) of 0.1 mg/kg bw/day by applying a safety factor of 100 to the NOAEL.
The lowest NOAEL for potential adverse effects of a single oral administration of folpet was 10 mg/kg bw/day based on the adverse effect on fetuses (hydrocephalus) in a developmental toxicity study in rabbits (the 2nd study in Table 2). FSCJ specified an acute reference dose (ARfD) of 0.1 mg/kg bw, for women who are or may be pregnant, by applying a safety factor of 100 to the NOAEL. In addition, FSCJ considered it unnecessary to specify ARfD for general population in view of the absence of adverse effects that would be likely to be elicited by a single oral administration of folpet.
| Species | Study | Dose (mg/kg bw/day) |
NOAEL (mg/kg bw/day) and critical endpoints1) |
| Rabbit | Developmental toxicity study (the 1st study) |
0, 10, 40, 160 | Maternal: 40 Maternal: Increased postimplantation loss rate |
| Developmental toxicity study (the 2nd study) |
0, 10, 20, 60 | Embryo/fetus: 10 Embryo/fetus: Hydrocephalus |
|
| ARfD | NOAEL: 10 SF: 100 ARfD: 0.1 |
||
| The critical study for setting ARfD | Developmental toxicity study in rabbits (the 2nd study) | ||
