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2018 Volume 6 Issue 3 Article ID: 2017018s
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of desmedipham (CAS No. 13684-56-5), a carbanilate herbicides, based on results from various studies. Major adverse effects of desmedipham were suppressed body weight, hemolytic anemia, methemoglobinemia and follicular cell hypertrophy in thyroid. Neither carcinogenicity, reproductive toxicity, nor genotoxicity relevant to human health was observed on desmedipham. Desmedipham, at the dose with maternal toxicity, caused external anomalies such as mandibular malformation and cleft palate, visceral anomalies such as ventricular septum defect, and skeletal anomalies such as defect of sternum and asymmetric alignment of seternebral hemicentres in developmental toxicity studies in rats. No teratogenetic effects were observed in rabbits. The lowest no-observed-effect level (NOAEL) obtained in all studies was 3.2 mg/kg bw/day in a two-year combined chronic toxicity/carcinogenicity in rats. FSCJ specified an acceptable (ADI) of 0.032 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for adverse effects elicited by a single oral administration of desmedipham was 90 mg/kg bw/day obtained from the developmental toxicity study in rabbits (the 2nd study in the Table 2). Consequently, FSCJ specified an acute reference dose (ARfD) of 0.9 mg/kg bw applying a safety factor of 100 to the NOAEL.
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of desmedipham (CAS No. 13684-56-5), a carbanilate herbicides, based on results from various studies.
The data used in the assessment include on the fate in animals (rats, cattle and chickens), fate in plants (sugar beets), residues in crops, subacute toxicity (rats and dogs), chronic toxicity (rats and dogs), combined chronic toxicity/carcinogenicity (rats), carcinogenicity (rats and mice), two-generation reproductive toxicity (rats), developmental toxicity (rats and rabbits), genotoxicity, and a mechanism of hemolytic anemia in dogs.
Major adverse effects of desmedipham were suppressed body weight, hemolytic anemia, methemoglobinemia and follicular cell hypertrophy in thyroid. Neither carcinogenicity, reproductive toxicity, nor genotoxicity relevant to human health was observed on desmedipham.
Desmedipham, at the dose with maternal toxicity, caused external anomalies such as mandibular malformation and cleft palate, visceral anomalies such as ventricular septum defect, and skeletal anomalies such as defect of sternum and asymmetric alignment of seternebral hemicentres in developmental toxicity studies in rats. No teratogenetic effects were observed in rabbits.
Based on the data on various studies, desmedipham (parent compound only) was identified as the substance relevant to the residue definition for dietary risk assessment in agricultural products.
The lowest no-observed-effect level (NOAEL) obtained in all studies was 3.2 mg/kg bw/day in a two-year combined chronic toxicity/carcinogenicity in rats. FSCJ specified an acceptable (ADI) of 0.032 mg/kg bw/day, applying a safety factor of 100 to the NOAEL.
The lowest NOAEL for adverse effects elicited by a single oral administration of desmedipham was 90 mg/kg bw/day obtained from the developmental toxicity study in rabbits (the 2nd study in the Table 2). Consequently, FSCJ specified an acute reference dose (ARfD) of 0.9 mg/kg bw applying a safety factor of 100 to the NOAEL.
| Species | Study | Dose(mg/kg bw/day) | NOAEL (mg/kg bw/day) and critical endpointsa |
| Rat | 13-week subacute toxicity study(the 1st study) | 0, 6, 30, 60, 300 ppm | M: 5.2F: 5.6F/M: Increase in MetHb, and Ret, etc. |
| M: 0, 0.5, 2.6, 5.2, 26F: 0, 0.5, 2.7, 5.6, 27 | |||
| 13-week subacute toxicity study(the 2nd study) | 0, 160, 800, 4 000 ppm | M: 10.6F: 12.3M: Congestive spleen, etc.F: Decrease in RBC, Ht and Hb, etc. | |
| M: 0, 10.6, 54, 275F: 0, 12.3, 60, 339 | |||
| One-year chronic toxicity study | 0, 100, 400, 1 200 ppm | M: 6.5F: 31.7F/M: Increase in T.Bil, etc. | |
| M: 0, 6.5, 25.2, 75.0F: 0, 7.9, 31.7, 97.1 | |||
| Two-year chronic toxicity/carcinogenicity study | 0, 60, 300, 1 500 ppm | M: 3.2F: 3.9F/M: Increase in MetHb and Ret, etc(Not carcinogenic) | |
| Chronic toxicity studyM: 0, 3.2, 15.7, 79.9F: 0, 3.9, 19.8, 101Carcinogenicity studyM: 0, 3.3, 16.1, 84.0F: 0, 4.1, 20.2, 104 | |||
| Two-year carcinogenicity study | 0, 100, 400, 1 200 ppm | M: 5.4F: 6.8M: Increase in alveolar macrophageF: Increase in T.Bil(Not carcinogenic) | |
| M: 0, 5.4, 21.6, 64.4F: 0, 6.8, 28.4, 86.6 | |||
| Two-generation reproductive toxicity study(the 1st study) | 0, 50, 250, 1 250 ppm | Parent and Offspring:PM: 4.0PF: 4.6F1M: 4.4F1F: 4.9Parent:F/M: Hemosiderin deposition in spleenOffspring: Suppressed body weight(No effect on reproduction) | |
| PM: 0, 4.0, 20.5, 106PF: 0, 4.6, 23.3, 120F1M: 0, 4.4, 22.5, 118F1F: 0, 4.9, 25.3, 130 | |||
| Two-generation reproductive toxicity study(the 2nd study) | 0, 100, 400, 1 200 ppm | Parent and Offspring:PM: 32.5PF: 38.8F1M: 37.6F1F: 42.5Parent:F/M: Suppressed body weight and decreased feed consumptionOffspring: lower weight (at birth) /Suppressed body weight (during lactation period)(No effect on reproduction) | |
| PM: 0, 8.04, 32.5, 97.0PF: 0, 9.67, 38.8, 118F1M: 0, 9.31, 37.6, 117F1F: 0, 10.5, 42.5, 128 | |||
| Developmental toxicity study(the 1st study) | 0, 10, 100, 1 000 | Maternal: 100Embryo/fetus: 100Maternal: Suppressed body weight and decreased feed consumptionEmbryo/fetus: External anomalies such as cleft palate and mandibular malformation | |
| Developmental toxicity study(the 2nd study) | 0, 10, 100, 500 | Maternal: 10Embryo/fetus: 100Maternal: Increase in MetHbEmbryo/fetus: lower body weight, etc. | |
| Developmental toxicity study(the 3rd study) | 0, 60, 250, 1 000 | Maternal: 60Embryo/fetus: 250Maternal: Increase in absolute spleen weightEmbryo/fetus: lower body weight and external anomalies such as cleft palate | |
| Mouse | Two-year carcinogenicity study |
0, 30, 150, 750 ppm | M: 21.7F: 30.8 |
| Intermittent sacrificeM: 0, 4.2, 21.7, 109F: 0, 5.8, 30.8, 145Carcinogenicity studyM: Increase in MetHb, etc.F: Decrease in Hb and Ht, etc. | M: 0, 4.24, 22.7, 141F: 0, 6.25, 34.3, 187(Not carcinogenic) | ||
| 80-week carcinogenicity study |
0, 400, 1 000, 2 500 ppm | M: 60.8F: 71.9 | |
| M: 0, 60.8, 153, 403F: 0, 71.9, 178, 503 | F/M: Necrosis of hepatocytes(Not carcinogenic) | ||
| Rabbit | Developmental toxicity study(the 1st study) | 0, 50, 150, 450 | Maternal: 150Embryo/fetus: 50Maternal: Suppressed body weight and feed consumptionEmbryo/fetus: lower body weight(Not teratogenic) |
| Developmental toxicity study(the 2nd study) | 0, 30, 90, 270 | Maternal: 30Embryo/fetus: 90Maternal: Increase in absolute weight of spleenEmbryo/fetus: lower body weight, delayed ossification of sternum and incompletely ossified phalanges(Not teratogenic) | |
| Dog | 13-week subacute toxicity study(the 1st study) | 0, 1, 5, 150 ppm | M: 4.97 |
| M: 0, 0.035, 0.17, 4.97F: 0, 0.035, 0.19, 5.50 | M: 4.97F: 5.50F/M: No toxicity | ||
| 13-week subacute toxicity study(the 2nd study) | 0, 100, 500, 1 500 ppm | M: 18.6F: 4.22 | |
| M: 0, 3.73, 18.6, 55.6F: 0, 4.22, 21.0, 62.2 | F/M: Follicular cell hypertrophy, etc. | ||
| One-year chronic toxicity study | 0, 300, 1 500, 7 500/5 000 b ppm | M: 9.7F: 10.4 | |
| M: 0, 9.7, 52.5, 168F: 0, 10.4, 57.4, 201 | F/M: Hemolytic anemia, etc. | ||
| Effect on MetHb formation | 0, 75, 150, 200, 300, 500, 1 500 ppm | M: 15.5F: 11.1 | |
| M: 0, 2.5, 5.1, 6.5, 9.7, 15.5, 45.0F: 0, 2.5, 4.3, 5.3, 11.1, 15.7, 49.2 | |||
| ADI | NOAEL: 3.2SF: 100ADI: 0.032 | ||
| The critical study for setting ADI | Two-year combined chronic toxicity/carcinogenicity study in rats | ||
M, Male; F, Female; F/M, both sexes; PM, Male in Parent (P) generation; PF, Female in P generation; F1M, Male in F1 generation; F1F, Female in F1 generation; ADI, Acceptable daily intake; cRfD, Chronic reference dose; SF, Safety factor; UF, Uncertainty factor; NOAEL, No-observed-adverse-effect level; -, NOAEL could not be specified; MetHB, methohemoglobin; Ret, Reticulocytes; Ht, Hemotocrit; T.Bil, Total bilirubin
a, The adverse effect observed at the lowest-observed-adverse-effect level (LOAEL); b, Administered at 7 500 ppm for the first 28 days, (reduced to) 5 000 ppm after 28 days
| Species | Study | Dose (mg/kg bw/day) |
NOAEL (mg/kg
bw/day) and critical endpointsa |
| Rat | Acute toxicity study | 5 000 | F/M: - F/M: Sedation, dyspnea, flexion, suppressed body weight, rough fur and blanching |
| Developmental
toxicity study (the 1st study) |
0, 10, 100, 1 000 | Maternal:
100 Maternal: Suppressed body weight and decreased feed consumption |
|
| Developmental
toxicity study (the 2nd study) |
0, 10, 100, 500 | Maternal:
100 Maternal: Suppressed body weight and decreased feed consumption |
|
| Developmental
toxicity study (the 3rd study) |
0, 60, 250, 1 000 | Maternal:
250 Maternal: Suppressed body weight and decreased feed consumption |
|
| Mouse | Acute toxicity study | 3 500 | M: 3 500 F: - F: Dyspnea, hypothermia and coma |
| Rabbit | Developmental
toxicity study (the 1st study) |
0, 50, 150, 450 | Maternal:
150 Maternal: Suppressed body weight and feed consumption |
| Developmental
toxicity study (the 2nd study) |
0, 30, 90, 270 | Maternal:
90 Maternal: Suppressed body weight and feed consumption |
|
| ARfD | NOAEL:
90 SF: 100 ARfD: 0.9 |
||
| The critical study for setting ARfD | Developmental toxicity study in rabbits (the 2nd study) | ||
ARfD, Acute reference dose; SF, Safety factor; NOAEL, No-observed-adverse-effect level; -, NOAEL could not be specified
a, The adverse effect observed at LOAEL
