Folpet (Pesticides)

Abstract

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.

Conclusion in Brief

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 2^nd study in Table 1), a developmental toxicity study in rats (the 1^st study in Table 1) and developmental toxicity studies in rabbits (the 1^st and 2^nd 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.

Table1. Levels relevant to toxicological evaluation of folpet.

Species	Study	Dose (mg/kg bw/day)	NOAEL (mg/kg bw/day) and critical endpoints1)
Rat	90-day subacute toxicity study (The 1st study)	0, 2 000, 4 000, 8 000 ppm M: 0, 116, 233, 456 F: 0, 126, 252, 482	M/F: - M/F: Accelerated diffuse keratitis of the fore-stomach, etc.
	90-day subacute neurotoxicity study (The 2nd study)	0, 2 500, 5 000, 10 000 ppm M: 0, 181, 363, 701 F: 0, 201, 397, 790	M/F: Suppressed body weight, etc. (No subacute neurotoxicity)
	Two-year chronic toxicity study	0, 250, 1 500, 5 000 ppm M: 0, 12.4, 83.2, 296 F: 0, 15.7, 104, 359	M: 12.4 F: 15.7 M/F: Accelerated diffuse keratosis of the fore-stomach
	Two-year combined chronic toxicity / carcinogenicity study	0, 200, 800, 3 200 ppm M: 0, 9.93, 40.0, 161 F: 0, 12.5, 50.5, 207	M: 40.0 F: 50.5 M/F: Hyperkeratosis of the fore-stomach, Acanthosis, etc. (Not carcinogenic)
	Two-year carcinogenicity study	0, 500, 1 000, 2 000 ppm M: 0, 27.6, 54.8, 108 F: 0, 33.5, 66.5, 133	M: 27.6 F: 33.5 M/F: Anterogastric epithelial hyperkeratosis, etc. (Not carcinogenic)
	Two-generation developmental toxicity study (The 1st study)	0, 200, 800, 3 600 ppm PM: 0, 14.4, 59.1, 263 PF: 0, 18.1, 73.2, 315 F1bM: 0, 22.0, 90.6, 421 F1bF: 0, 23.4, 94.8, 434	Parent and offspring PM: 59.1 PF: 73.2 F1M: 90.6 F1F: 94.8 Parent and offspring: Suppressed body weight (No effect on reproduction)
	Two-generation developmental toxicity study (The 2nd study)	0, 250, 1 500, 5 000 ppm PM: 0, 18.9, 112, 370 PF: 0, 22.5, 133, 436 F1M: 0, 25.2, 150, 520 F1F: 0, 28.4, 168, 56	Parent and Offspring PM: 18.9 PF: 22.5 F1M: 25.2 F1F: 28.4 Offspring: Suppressed body weight (No effect on reproduction)
	Developmental toxicity study (The 1st study)	0, 10, 60, 360	Maternal: 10 Embryo/fetus: 360 Maternal: Suppressed body weight, etc. Embryo/fetus: No toxicity (Not teratogenic)
	Developmental toxicity study (The 2nd study)	0, 150, 550, 2 000	Maternal: 150 Embryo/fetus: 150 Maternal: Decreased pregnant uterus weight, etc. Embryo/fetus: Delayed ossification, etc. (Not teratogenic)
	Developmental toxicity study (The 3rd study)	0, 20, 100, 800	Maternal: 100 Embryo/fetus: 800 Maternal: Suppressed body weight, etc. Embryo/fetus: No toxicity (Not teratogenic)
Mouse	Two-year carcinogenicity study (The 1st study)	0, 1 000, 3 500, 7 000 ppm M: 0, 123, 564, 1 260 F: 0, 141, 608, 1 300	M/F: - M/F: Accelerated diffuse keratitis of the fore-stomach mucosa, etc. (M/F: Increased duodenal adenoma and carcinoma F: Increased fore-stomach mucosal papilloma and carcinoma)
	Two-year carcinogenicity study (The 2nd study)	0, 1 000, 5 000, 12 000 Ppm M: 0, 93.0, 502, 1 280 F: 0, 95.5, 515, 1 280	M/F: - M/F: duodenal mucosal hyperplasia (M/F: Increased duodenal adenoma and adenocarcinoma M: Increased jejunal adenocarcinoma F: Increased jejunal adenoma and adenocarcinoma)
	Two-year carcinogenicity study (The 3rd study)	0, 150, 450, 1 350 ppm M: 0, 16.2, 46.7, 151 F: 0, 16.0, 51.3, 154	M: 46.7 F: 51.3 M: Suppressed body weight, etc. F: Keratoacanthoma cell hyperplasia of the stomach, etc. (F: Increased corneal squamous papillomas of the stomach)
Rabbit	Developmental toxicity study (The 1st study)	0, 10, 40, 160	Maternal and Embryo/fetus: 10 Maternal: Suppressed body weight Fetus: The 13th rib, etc. (Not teratogenic)
	Developmental toxicity study (The 2nd study)	0, 10, 20, 60	Maternal and Emryo/fetus: 10 M: Suppressed body weight, etc. Embryo/fetus: Hydrocephalus, etc. (Teratogenicity at the maternally toxic dose)
Dog	90-day subacute toxicity study	0, 20, 50, 500	M/F: - M/F: Centrilobular hepatocell vacuolation
	One-year chronic toxicity study (The 1st study)	0, 325, 650, 1 300	M: - F: 325 M: Decreased TP, etc. F: Suppressed body weight, etc.
	One-year chronic toxicity study (The 2nd study)	0, 10, 60, 120	M/F: 10 M/F: Suppressed body weight gain, etc.
ADI			NOAEL: 10 SF: 100 ADI: 0.1
Critical study (studies) for setting ADI			A one-year chronic toxicity study (The 2nd study) in dogs A developmental toxicity study (The 1st study) in rats A developmental toxicity study (The 1st study) and (The 2nd study) in rabbits

M, Male; F, Female; M/F, both sexes; PM, Male in P (Parent) generation; PF, Female in P generation; F₁M, Male in F₁ generation; F₁F, Female in F1 generation;-, NOAEL could not be specified; ADI, Acceptable daily intake; SF, Safety factor

¹⁾, The adverse effect observed at the lowest-observed-adverse-effect level (LOAEL)

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 2^nd 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.

Table 2. Potential adverse effects of a single oral administration of folpet (Women who are or may be pregnant) .

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)

ARfD, Acute reference dose; SF, Safety factor
¹⁾ The adverse effect observed at LOAEL

This is an English translation of excerpts from the original full report (March 2017−FS/134/2017). Only original Japanese texts have legal effect. The original full report is available in Japanese at http://www.fsc.go.jp/fsciis/attachedFile/download?retrievalId=kya20060718035&fileId=201