Table 1. Levels relevant to toxicological evaluation of MGA .
| Species | Study | Dose (mg/kg bw/day) |
NOAEL (mg/kg bw/day) |
|---|---|---|---|
| Mouse | 10-day subacute toxicity study | 0.033, 0.166, 0.33, 1.3, 3, 5, 7.5 (Oral administration) | 4.2 (Minimum effective dose) Abnormal estrous cycle |
| 20-day subacute toxicity study (the 1st study) |
0, 0.25, 0.5, 2.5, 5, 10, 15, 20, 25, 40 (Dietary administration) | N/A Mammary gland development in the control group of C3Han/f mice |
|
| 20-day subacute toxicity study (the 2nd study) |
0, 0.5, 1.5, 2.5, 5, 10, 25 (Dietary
administration) + MEA |
N/A Increased serum prolactin concentrations and mammary gland development |
|
| 20-21day subacute toxicity study | 0, 0.05, 0.25, 0.5, 1.5, 2.5, 5, 25 (Dietary administration) | 1.5 Increased body weight |
|
| 30-day subacute toxicity study | 0, 1, 3, 10, 30 (Gavage administration) |
1 Absence of corpora lutea |
|
| 24.5-month carcinogenicity study | 0, 0.017, 17 (Dietary administration) |
- A slight and nonsignificant increase in the incidence of mammary adenocarcinomas |
|
| 27-month carcinogenicity study | 0, 0.5, 1, 1.5, 2.5, 5, 10, 15, 25 (Dietary administration) | 1 Increase in mammary tumor incidence |
|
| 29-month carcinogenicity study | 0, 0.5, 1.5, 2.5, 5, 10, 25 (Dietary administration) + MEA 100 mg/animal /day (Subcutaneous administration) |
0.5 Increase in mammary tumor |
|
| 33-month carcinogenicity study | 0, 0.017, 17 (Dietary administration) |
- Increase in the incidence of mammary adenocarcinomas |
|
| Rat | 28-day subacute toxicity study | 0, 1, 3, 10 (Gavage administration) |
N/A Decreased weights of the adrenals, ovaries, and testes |
| 90-day subacute toxicity study (the 1st study) |
0, 0.015, 0.15, 0.3 (Dietary administration) |
0.015 (Minimum effective
dose) Histopathological change (Enlarged mammary glands) |
|
| 90-day subacute toxicity study (the 2nd study) |
0, 0.055 (Dietary administration) | N/A Decreased weights of the adrenals, ovaries, and uterus |
|
| One-generation reproductive toxicity study |
0, 0.03, 0.06, 0.13, 0.25, 1
(Dietary administration) |
0.03 Reproductive toxicity |
|
| Developmental toxicity study (the 1st study) |
2 (Subcutaneous administration) | N/A | |
| Developmental toxicity study (the 2nd study) |
0, 15, 25, 50, 100 (Subcutaneous administration) | N/A Lack of information on the toxicokinetics of the sustainable release formulation |
|
| Rabbit | 22-day subacute toxicity study | 20 (Intramuscular administration) | N/A Increased Chol and Glu, elevated LDH and ALP levels, enlarged liver, muscular atrophy and atrophic change of adrenals, glycogen deposits, swollen hepatocytes with glycogen deposits and cytoplastic vacuole, decreased granulation of the zona glomerulosa of the adrenals |
| Developmental toxicity study (the 1st study) |
0, 0.016, 0.064, 0.16, 0.4, 0.8, 1.6, 3.2,
6.4 (Dietary administration) |
Offspring: 0.4 Developmental toxicity (Decreased number of live fetuses and mean litter and fetal weights) |
|
| Developmental toxicity study (the 2nd study) |
0, 25, 50 (Intramuscular
administration) 0, 5, 15 (Intramuscular administration) |
N/A Lack of information on the toxicokinetics of the sustainable release formulation |
|
| Dog | 29-day subacute toxicity study | 0, 1, 3, 10 (Oral administration) | N/A Slight decrease in body weights, increase in absolute/relative liver weights, and reduction in adrenal weights, cells with a pale cytoplasm that did no stain for fat in the liver, renal tubular epithelium, and zona fasciculata of the adrenals |
| Two-year chronic toxicity study | 0, 0.001, 0.002, 0.008/0.004 (Oral administration) | 0.001 Effects on endocrine organs |
|
| One-generation repro ductive toxicity study (the 1st study) |
0.001, 0.005, 0.01, 0.02, 0.04, 0.08 (Oral administration) | N/A Insufficient data to specify a NOAEL |
|
| One-generation reproductive toxicity study
(the 2nd study) |
0.1/body (Oral administration) | N/A Increased body weight of fetus |
|
| One-generation reproductive toxicity study
(the 3rd study) |
0, 0.001, 0.002, 0.008/0.004 (Oral administration) | 0.002 Fertility of dams (Disturbance of the estrous cycle and dystocia) |
|
| Monkey | One-menstrual-cycle study (the 1st study) |
0, 0.0015, 0.015, 0.075, 0.15 (Oral administration) | 0.0015 Suppression of ovulation |
| One-menstrual-cycle study (the 2nd study) |
0, 0.0025, 0.005, 0.01 (Oral administration) |
N/A AUC for LH was decreased |
|
| Three-menstrual-cycle study | 0, 0.005, 0.01, 0.025 (Oral administration) |
0.005 (Minimum effective
dose) Changes in menstrual cycle |
|
| Cattle | 16-day administration study | 0.00016, 0.00031, 0.00063, 0.0013, 0.0025,
0.005, 0.01, 0.02 (Dietary administration) |
N/A Disturbance of the estrous cycle |
| Administration study (the 2nd study) |
0, 0.0018 (Dietary administration) | N/A Hormonal response observed at higher doses |
|
| One-generation reproductive toxicity study
(the 1st study) |
0, 0.002 (Dietary administration) | - No abnormality observed |
|
| One-generation reproductive toxicity study
(the 2nd study) |
0, 1 mg/head (Dietary administration) |
- No abnormality observed |
|
| Toxicological ADI | 0–0.03 µg/kg bw/day Minimal effects on menstral cycle in monkeys Lowest LOEAL: 5 µg/kg bw/day SF: 200 |
||
| The critical study for setting the ADI | Three menstrual-cycle study in monkeys | ||
| ADI | 0–0.03 µg/kg bw/day | ||
-, NOEL could not be specified