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EC number: 701-068-0
CAS number: 2156592-58-2
Groups of 10 rats (Crl:CD (SD) BR) per sex were treated with
dosages of 0, 12.5, 50, and 150 mg/kg bw/day of Genamin TA 100 by gavage
(administration volume 10 ml/kg bw/day) using sesame oil as a vehicle.
Males were treated daily from 14 days prior to mating until the end of
the mating period for a maximum of 28 days. Females were treated daily
for 14 days before start of the mating period, throughout the same,
during pregnancy and until day 3 of lactation. The animals were mated
one male with one female.
At daily doses of 150 mg/kg bw 6/10 males and 5/10 females died
between day 9 and day 25 of treatment (during the premating and mating
period). At daily doses of 50 mg/kg bw 1/10 males and 1/10 females died
on day 13 respectively on day 24 of treatment. No animals died at 12.5
mg/kg bw/day, and in the control group 1 female died by accident.
Clinical observations at 150 mg/kg bw/day revealed salivation
after treatment, hunched posture and in some cases soft stools and
piloerection. The only clinical sign present at 50 mg/kg bw/day was
salivation. No changes were seen at 12.5 mg/kg bw/day.
Body weight loss of about 22 g at the 150 mg/kg bw dose group and
statistically significant (p > 0.01) lower body weight gain at the 50
mg/kg bw dose group during the premating period together with a lower
mean food consumption was observed in the males. Also in the females
body weight loss of about 17 g at the 150 mg/kg bw dose group and
statistically significant lower body weight gain at the 50 mg/kg bw dose
group together with a lower mean food consumption during the premating
period was observed.
At sacrifice of the parental animals organ weights of ovaries,
testes and epididymides were determined from all experimental groups.
Histopathology was carried out on testes, epididymides and ovaries of
the controls and of the animals of the 150 mg/kg bw dose group. A
statistically significant(p> 0.01) lower absolute and relative weight of
epididymides and a statistically significant(p> 0.01) higher value of
relative testis weight was observed at 150 mg/kg bw/day. No significant
differences were noted in ovary weights among the various experimental
groups. Histopathology of testes and epididymides of high dose group
animals did not show any compound-related changes. In particular, no
changes were seen in the testicular staging performed in the
PAS-hematoxylin stained sections of final sacrificed animals of control
and of the high dose groups. In the ovaries, moderate increased
frequency of atrophic corpora lutea was seen in the animals of the high
dose group which died or were sacrificed, compared to the controls, this
finding was considered a secondary effect to the decrease in body weight
growth induced by treatment in this group.
At the dosages of 150 mg/kg bw/day only 3 females out of 7 mated
females had positive vaginal smears and of these only one was pregnant,
but with only implantation sites and no live pups. At this dosage level
also the mean pre-coital interval was longer (13.4 days) than that of
the control group (2.3 days). With regard to the mating index in the
control, the 12.5 and the 50 mg/kg bw dose level groups 9/9 (100%), 9/10
(90%) and 9/9 (100%) mated females were sperm positive. With regard to
the fertility index 9/9 (100%), 8/10 (80%) and 7/9 (78%) of the mated
females became pregnant in the control, the 12.5 and the 50 mg/kg bw
dose level groups. Mean pre-coital time and parturition were unaffected
in the low and mid dose treated groups.
With regard to the conception rate in the control, the 12.5 and
the 50 mg/kg bw dose level groups 9/9 (100%), 8/9 (89%) and 7/9 (78%) of
the sperm positive females became pregnant and delivered live pups.
Numbers of corpora lutea had not been determined during this study.
Thus, any pre-implantation loss was not evaluated. Staining for the
presence of implantation sites was only performed with the uteri of
apparently non-pregnant females. The mean number of visible implantation
sites per dam in the control, the 12.5 and the 50 mg/kg bw dose level
groups were 17.6, 13.9 and 15.0. There were no stillborns or litters
with only implantations in the control, low, and mid dose groups. The
mean number of total pups born per litter was 16.9, 12.3 and 14.3 in the
control, the 12.5 and the 50 mg/kg bw/day dose groups. Thus, the mean
litter index for post-implantation loss was calculated to 3.4, 9.9 and
4.5% in the control, the low and the mid dose groups.
No effects were noted on the pup sex ratio. No abnormalities were
observed in any pup either at birth or at autopsy on day 4 of lactation
neither in the 12.5 nor in the 50 mg/kg bw/day treated groups. Lower
mean values of live born per litter and of pups per litter alive at day
4 were found for both the low and the intermediate dose groups in
comparison to those of the control group, however, the decreases were
not dose dependent and the differences were statistically significant
for the 12.5 mg/kg bw dose group only. Thus, these findings were
considered unlikely to be related to the compound. A slightly lower pup
body weight was observed in the 50 mg/kg bw/day treated group in
comparison with the control group at birth and at day 4 of lactation but
not for the pups of the 12.5 mg/kg bw/day treated group. Based on
general toxicity findings a NOEL(systemic toxicity) of 12.5 mg/kg/day
can be derived from stis study. Additionally, based on findings of a
lower fertility index and a slightly lower conception rate at the mid
dose level a NOEL(fertility) of 12 .5 mg/kg body weight per day is
during an oral 28-day study (OECD TG 407) with the same test substance
Genamin TA 100 in rats (see section 7.5.1) also reproductive organ
weights and reproductive organ histopathology of testes and
epididymides, as well as organ weights of ovaries and uteri had been
investigated. No substance-related findings had been observed during
this study on these organs at oral doses up to and including 150 mg/kg
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