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EC number: 246-495-9
CAS number: 24851-98-7
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.
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
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
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.
reductions in maternal body weight gain occurred in the 120 mg/kg/day
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 (p≤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
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
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.
On the basis of
these data, the maternal no-observable-effect-level (NOAEL) of
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
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