Abstract
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of picarbutrazox (CAS No.500207-04-5), a methyltetrazole-type fungicide, based on results from various studies. Major adverse effects of picarbutrazox were observed as hepatocellular hypertrophy and hypertrophy of follicular epithelial cells in rats. None of neurotoxicity, reproductive toxicity, teratogenicity and genotoxicity were detected in the experiments described above. Picarbutrazox (parent compound only) and its metabolite B were identified as the relevant substance for the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all studies was 2.34 mg/kg bw/day in a two-year combined chronic toxicity/carcinogenicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 0.023 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. FSCJ judged it unnecessary to specify an acute reference dose (ARfD), since no adverse effects would be likely to be elicited by a single oral administration.
Conclusion in Brief
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of picarbutrazox (CAS No.500207-04-5), a methyltetrazole-type fungicide, based on results from various studies.
The data used in the assessment include fate in animals (rats), fate in plants (paddy rice, cucumbers and others), residues in crops, subacute toxicity (rats and dogs), chronic toxicity (dogs), combined chronic toxicity/carcinogenicity (rats), carcinogenicity (mice), two-generation reproductive toxicity (rats), developmental toxicity (rats and rabbits) and genotoxicity, and also their mechanisms.
Major adverse effects of picarbutrazox were observed as hepatocellular hypertrophy and hypertrophy of follicular epithelial cells in rats. None of neurotoxicity, reproductive toxicity, teratogenicity and genotoxicity were detected in the experiments described above.
Significant increases in the incidence of follicular cell adenoma were observed in both male and female rats in a two-year combined chronic/carcinogenicity study. Non-genotoxic mechanism is likely to be involved in tumor induction, and it was, thus, enable to establish a threshold dose in the assessment. The mechanism study suggested that increased incidence of follicular cell adenoma was secondary effect of prolonged TSH stimulation on follicular epithelial cells through induction of hepatic UDP-GT to reduce blood T4 levels.
Studies on fate in plants indicated the appearance of metabolite B (E-stereoisomer) (> 10% TRR) in the edible parts and livestock feeds. Metabolite B, showing the toxicity similar to the parent, was detected at residue levels equal or higher compared to the parent. On the basis of the above results, picarbutrazox (parent compound only) and its metabolite B were identified as the relevant substance for the residue definition for dietary risk assessment in agricultural products.
The lowest no-observed-adverse-effect level (NOAEL) obtained in all studies was 2.34 mg/kg bw/day in a two-year combined chronic toxicity/carcinogenicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 0.023 mg/kg bw/day, applying a safety factor of 100 to the NOAEL.
FSCJ judged it unnecessary to specify an acute reference dose (ARfD), since no adverse effects would be likely to be elicited by a single oral administration. (table 1) (table 2) (table 3)
Table 1. relevant to toxicological evaluation of picarbutrazox.
| Species | Study | Dose (mg/kg bw/day) |
NOAEL (mg/kg bw/day) |
LOAEL (mg/kg bw/day) |
Critical endpoints1) |
|---|---|---|---|---|---|
| Rat | 28-day toxicity study |
0, 200, 2,000, 20,000 ppm (M: 0, 15.1, 150, 1,440; F: 0, 16.5, 163, 1,570) |
M: 15.1 F: 16.5 |
M: 150 F: 163 |
M/F: Centrilobular hypertrophy of hepatocytes, hypertrophy of thyroid follicular epithelial cells, etc |
| 90-day toxicity study (the 1st studya) |
0, 50, 150, 500, 1,000 ppm (M: 0, 3.5, 10.5, 34.5, 68.1; F: 0, 3.9, 12.0, 40.3, 77.5) |
M: 10.5 F: 12.0 |
M: 34.5 F: 40.3 |
M/F: Increased absolute/ relative thyroid weights, etc |
|
| 90-day toxicity study (the 2nd studya) |
M: 0, 5, 10, 20, 200 ppm (0, 0.3, 0.6, 1.2, 11.5) F: 0, 10, 20, 200, 1,000 ppm (0, 0.7, 1.4, 14.1, 69.8) |
M: 11.5b F: 14.1 |
M: - F: 69.8 |
F: Increased absolute/relative
liver and thyroid weights |
|
| Two-year combined chronic toxicity/ carcinogenicity studya |
0, 30, 60, 200, 660 ppm (M: 0, 1.44, 2.34, 7.82, 26.9; F: 0, 1.84, 3.01, 10.2, 34.6) |
Chronic toxicity M: 2.34 F: 3.01 |
Chronic toxicity M: 7.82 F: 10.2 |
M: Increased absolute/relative
thryoid weights F: Vacuole in perilobular hepatocyte, etc |
|
| Carcinogenicity M: 7.82 F: 10.2 |
Carcinogenicity M: 26.9 F: 34.6 |
M/F: Follicular cell adenoma in the thyroid |
|||
| Two-generation of reproductive toxicity studya |
0, 20, 50, 200, 800 ppm (PM: 0, 1.2, 2.9, 11.6, 46.4; PF: 0, 1.6, 4.0, 16.3, 62.6; F1M: 0, 1.3, 3.2, 13.0, 52.8; F1F : 0, 2.0, 5.0, 19.9, 75.0) |
Parent: PM: 2.9 PF: 4.0 Offspring: F1M: 3.2 F1F: 5.0 Reproduction: - |
Parent: PM: 11.6 PF: 16.3 Offspring: F1M: 13.0 F1F: 19.9 Reproduction: - |
Parent: M/F: Increased liver weight, etc Offspring: Increased absolute liver weight Reproduction: No effect on reproduction |
|
| Developmental toxicity studyc | 0, 10, 100, 1,000 | Maternal: 100 Embryo/fetus: 1,000b |
Maternal:
1,000 Embryo/fetus: - |
Maternal: Decreased food
consumption, increased absolute/relative liver weights Embryo/fetus: No toxicity (Not teratogenic) |
|
| Mouse | 18-month carcinogenicity studya |
0, 30, 180, 1,000 ppm (M: 0, 3.38, 21.1, 117; F: 0, 3.87, 23.2, 134) |
Chronic toxicity M: 3.38 F: 23.2 |
Chronic toxicity M: 21.1 F: 134 |
M: Periportal/diffuse
hepatocellular hypertrophy, etc F: Periportal vacuoles in hepatocyte, etc |
| Carcinogenicity M: 117b F: 134b |
Carcinogenicity M: - F: - |
Not carcinogenic in mice | |||
| Rabbit | Developmental toxicity studyc | 0, 10, 100, 500, 1,000 | Maternal: 500 Embryo/fetus: 500 |
Maternal:
1,000 Embryo/fetus: 1,000 |
Maternal: Depressed body weight gain, lower feed consumption, etc Embryo/fetus: Increased number of sterna, etc (Not teratogenic) |
| Dog | 90-day toxicity studya |
0, 400, 4,000, 40,000 ppm (M: 0, 13.3, 133, 1,510; F: 0, 13.5, 130, 1,790) |
M: 13.3 F: 13.5 |
M: 133 F: 130 |
F/M: Diffuse hepatocellular
hypertrophy, etc |
| One-year chronic toxicity studya |
0, 200, 1,50, 10,000 ppm (M: 0, 5.13, 40.5, 327; F: 0, 5.23, 43.3, 298) |
M: 5.13 F: 5.23 |
M: 40.5 F: 43.3 |
F/M: Diffuse hepatocellular
hypertrophy, etc |
|
| ADI | NOAEL: 2.34 SF: 100 ADI: 0.023 |
||||
| The critical study for setting ADI | A two-year combined chronic toxicity/carcinogenicity study in rats | ||||
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; -, No effect observed at the highest dose tested; ( ) at dose, mg/kg bw/day; 1), the adverse effect observed at LOAEL; a, Dietary administration; b, Highest dose tested; c, Gavage administration; SF, Safety factor.
Table 2. Toxicological profiles and critical end-points for setting guidance values for exposure to picarbutrazox.
| Absorption, distribution, excretion and metabolism in mammals | |
| Rate and extent of oral absorption | Absorbed within 24 h at a low dose (> 91.6% in males and > 85.6% in females) |
| Distribution | Rapid distribution, various organs, the highest in the liver in both sexes |
| Potential for accumulation | No potential for accumulation |
| Rate and extent of excretion | Rapidly excreted into urine or feces (> 90% within 48 h) |
| Metabolism in animals | Hydroxylation, conjugation, cyclization and cleavage |
| Toxicologically significant compounds for animals and plants | Picarbutrazox, Metabolite B (E-stereoisomer) |
| Acute toxicity | |
| LD50, oral | > 2,000 mg/kg bw (rat) |
| LD50, dermal | > 2,000 mg/kg bw (rat) |
| LC50, inhalation | > 5.20 mg/L (rat) |
| Dermal irritation | Not irritating (rabbit) |
| Ocular irritation | Slightly irritating (rabbit) |
| Dermal sensitization | Not sensitizing (maximization test) (guinea-pig) |
| Short-term studies of toxicity | |
| Target/critical effect | Liver/Hepatocellular hypertrophy (rat, dog), Thyroid/Follicular cell hypertrophy (rat) |
| Lowest relevant oral NOAEL | 10.5 mg/kg bw/day (rat) |
| Long-term studies of toxicity and carcinogenicity | |
| Target/critical effect | Liver/Hepatocellular hypertrophy (mouse, rat, dog), Thyroid/Follicular cell hypertrophy (rat) |
| Lowest relevant NOAEL | 2.34 mg/kg bw/day (rat) |
| Carcinogenicity | Carcinogenic in rats, but not in mice |
| Target/critical effect | Thyroid/Follicular cell adenoma (rat) |
| Lowest relevant NOAEL for carcinogenicity | 7.82 mg/kg bw/day (rat) |
| Genotoxicity | |
| No evidence of genotoxicity | |
| Reproductive toxicity | |
| Target/critical effect | Liver/Hepatocellular hypertrophy, Thyroid/Follicular cell hypertrophy (rat) |
| Lowest relevant parental NOAEL | 2.9 mg/kg bw/day (rat) |
| Lowest relevant offspring NOAEL | 3.2 mg/kg bw/day (rat) |
| Lowest relevant reproductive NOAEL | 46.4 mg/kg bw/day (the highest dose tested) (rat) |
| Developmental toxicity | |
| Target/critical effect | Increased number of sterna (rabbit) |
| Lowest relevant maternal NOAEL | 100 mg/kg bw/day (rat) |
| Lowest relevant embryo/fetus NOAEL | 1,000 mg/kg bw/day (the highest dose tested) (rat) |
| Lowest relevant maternal NOAEL | 500 mg/kg bw/day (rabbit) |
| Lowest relevant embryo/fetus NOAEL | 500 mg/kg bw/day (rabbit) |
| Neurotoxicity | |
| Acute neurotoxicity NOAEL | 2,000 mg/kg bw (the highest dose tested) (rat) |
| Subchronic neurotoxicity NOAEL | No data |
| Other toxicological studies | |
| Studies on toxicologically relevant metabolites | Metabolite B (E-stereoisomer) Oral LD50 > 2,000 mg/kg bw (rat) No evidence of genotoxicity |
| Mechanistic/mode of action study | Increased incidence of follicular cell adenoma was secondary effect of prolonged TSH stimulation on follicular epithelial cells through induction of hepatic UDP-GT to reduce blood T4 levels |
Table 3. Summary.
| Value | Study | Safety factor | |
|---|---|---|---|
| Picarbutrazox | |||
| ADI | 0.023 mg/kg bw/day | A two-year combined chronic toxicity/carcinogenicity study (rat) | 100 |
| ARfD | Unnecessary | - | - |
Acknowledgement:
FSCJ wishes to thank the members of Expert Committee on Pesticides for the preparation of the original full report. Suggested citation: Food Safety Commission of JAPAN. Picarbutrazox: Summary. Food Safety. 2016; 4 (2): 56–60. doi:10.14252/foodsafetyfscj.2016008s
This is an English translation of excerpts from the original full report (May 2016−FS/334/2016). 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=kya20160104488& fileId=201.