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Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
100 mg/kg bw/day
Additional information

The results of a 90-day repeat dose toxicity study in the rat revealed no evidence to toxicity up to 100 mg/kg bw to the reproductive organs of the males or female rats used in the study. The study examined the secondary sex organs in great detail and no adverse effects were detected. In a prenatal developmental toxicity study no adverse effects were detected up to 120 mg/kg bw in the reproductive parameters and the offspring including no evidence of any change in the sex ratio.On a weight of evidence basis, the negative data of the 90-day repeat dose toxicity study and the negative data of a developmental toxicity study are together consider sufficient to obviate the need for a 2-generation reproductive study. In addition, the substance is not genotoxic.

Based on these study results, and also on the grounds on animal welfare, the conclusion is made that the performance of a 2-generation study is not warranted.



Short description of key information:
The reults of a 90-day repeat dose toxicity study in the rat revealed no evidence to toxicity to the reproductive organs of the males or female rats used in the study The study examined the secondary sex organs in great detail and no adverse effects were detected. In a prenatal developmental toxicity study no adverse effects were detected in the offspring including no evidence of any change in the sex ratio.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
120 mg/kg bw/day
Additional information

An oral (gavage) developmental toxicity study of methyldihydrojasmonate (MDJ) in rats was performed according to the following FDA Guideline for Industry: Detection of toxicity to reproduction for medicinal products, ICH-S5A; September, 1994, Rockville (MD).

 

One hundred presumed pregnant Crl:CD(SD) rats were randomly assigned to four dosage groups (Groups I through IV), 25 rats per group. The test article, MethylDihydrojasmonate (MDJ), or the vehicle, Corn Oil, was administered orally viagavageonce daily on days 7 through 20 of presumed gestation (DGs 7 through 20) at dosages of 0 (Vehicle), 40, 80 and 120 mg/kg/day to rats in Groups I through IV, respectively. The dosage volume (10mL/kg) was adjusted daily on the basis of the individual body weights recorded before intubation. The rats were administered the test article and/or the vehicle once daily at approximately the same time each day. All rats were examined for clinical observations of effects of the test article, abortions, premature deliveries and deaths before dosage, between one and two hours following dosage and once daily during thepostdosageperiod. Body weights were recorded on DG 0 and daily during the dosage andpostdosageperiods. Feed consumption values were recorded on DGs 0, 7, 10, 12, 15, 18, 20 and 21. All rats were sacrificed on DG 21, Caesarean-sectioned and a gross necropsy of the thoracic, abdominal and pelvic viscera performed. All fetuses were weighed and examined for sex and gross external alterations. Approximately half of the fetuses in each litter were examined for soft tissue alterations (by dissection) or skeletal alterations (alizarin red S-staining).

 

All prepared formulations were acceptable for use on this study.

All rats survived to scheduled sacrifice on DG 21. One dam in the 80 mg/kg/day dosage group prematurely delivered its litter on DG 21, a non dosage dependent event unrelated to MDJ.

 

The 120 mg/kg/day dosage of MDJ was associated with an increase in sparse hair coat and a significant increase in ungroomed coat that occurred at the end of the dosage period. Two rats in the 120 mg/kg/day dosage group each had tan areas in the liver lobes and a pale spleen. All other clinical and necropsy observations were considered unrelated to treatment with MDJ.

 

Toxicologically important reductions in maternal body weight gain occurred in the 120 mg/kg/day dosage group.

 

Both the 80 and 120 mg/kg/day dosage groups lost weight after the initial dosage was given (DGs 7 to 8), clear reductions in weight gain continued throughout the dosage period only in the 120 mg/kg/day dosage group. The 120 mg/kg/day dosage group had significantly reduced (pā‰¤0.01) body weight gain on DGs 8 to 9 and DGs 7 to 10 and reduced weight gain on DGs 10 to 12. Average maternal body weights were reduced in the 120 mg/kg/day dosage group on DGs 7 through 21; these reductions were statistically significant on DGs 11 through 15, as comparison to the vehicle control group values.

 

Absolute and relative maternal feed consumption values were significantly reduced in the 120 mg/kg/day dosage group for the entire dosage period (calculated as DGs 7 to 21), as compared with the vehicle control group value. Within the dosage period, these values were reduced or significantly reduced in the 120 mg/kg/day dosage group at all tabulated intervals, as compared with the vehicle control group values, with the most severe reductions present on DGs 7 through 15.

 

No Caesarean-sectioning or litter parameters were affected by dosages of MDJ as high as 120 mg/kg/day.

Although the 120 mg/kg/day dosage group tended to have reduced fetal body weights (combined fetal body weights averaged 5.12 g, as compared with 5.24 g for the vehicle control group), the reductions in fetal body weights were not considered to be of toxicological importance because the values did not significantly differ from the vehicle control group values and were within the historical ranges of the Testing Facility.

 

No gross external, soft tissue or skeletal fetal alterations (malformations or variations) or differences in ossification site averages were attributable to dosages of MDJ as high as 120 mg/kg/day. All values were within the historical ranges of the Testing Facility.

 

Conclusions On the basis of these data, the maternal no-observable-effect-level (NOAEL) of MethylDihydrojasmonate (MDJ) is 80 mg/kg/day. The 120 mg/kg/day dosage of MDJ caused maternal weight loss after the initial dosage and reduced maternal body weight gains and body weights during the dosage period as well as reduced absolute and relative maternal feed consumption values for the entire dosage period.

 

The developmental NOAEL is greater than 120 mg/kg/day. The only observation associated with the 120 mg/kg/day dosage of MDJ was a minimal reduction in fetal body weight that was not considered to be toxicologically important because the value was not statistically significant, as compared with the vehicle control group value, and was within the historical range of the Testing Facility. Based on these data,MDJ should not be identified as a developmental toxicant.

Justification for classification or non-classification