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EC number: 809-920-4
CAS number: 1047637-37-5
Table 22.214.171.124 Summary of the
significant absolute and relative organ weight changes in male parental
animals in the 2-generation reproductive toxicity study
A: absolute weight; R: relative weight
Table 126.96.36.199 Summary of the
significant absolute and relative organ weight changes in parental
females in the 2-generation reproductive toxicity study
A: absolute weight; R: relative weight
Table 188.8.131.52 Mean terminal body
weights and significant organ weights for males of F0 and F1 generations
Mean terminal body weight
Mean absolute organ weight (g)
Mean organ weights relative to terminal body weight (g/kg bw)
*/**/*** statistically significantly
different to the control group p 0.05/ 0.01/ 0.001
Table 184.108.40.206 Mean terminal body
weights and significant organ weights for females of F0 and F1
**/*** statistically significantly
different to the control group p 0.01/ 0.001
Table 220.127.116.11 Delivery, pup and litter
data for F0 and F1 generations
Mean no. live pups/litter (PN1)
Sex ratio on PN1 (M/F)
No. pups alive Day 21
Mean no. of pups delivered
No. of liveborn
No. of stillborn
No. of pups lost (dying, missing and/ or cannibalized) on:
*/**/*** statistically significantly
different to the control group p 0.05/ 0.01/ 0.001. 1 due to
1 animal with 11 of 12 pups stillborn
2 statsitcal significance
due to high number of males and low number of females in the control. No
18.104.22.168 Clinical observations in pups
of F0 and F1 generations on Days 1-21 of lactation
figures in brackets represent the
number of litters with pups showing the observation.
the 2-generation study groups of 28 male and female Wistar rats
received daily dietary doses of
approximately 0, 28.9, 85.8 and 261.9 mg/kg bw (males) and 0, 33.2,
97.1 and 302.3 mg/kg bw (females) over two successive generations.
The dose selection was
based on a preliminary dose range finding study with the same species,
strain and route of administration.
animals were fed diets containing the test substance from the start of
the study, during
the premating period of at least 10 weeks, during gestation and
lactation until sacrifice.
The concentration of the test substance in the diets was adjusted
during the different periods of the study to maintain the dose rates
in the face of differing food consumption rates. Dams were allowed to
raise one litter. At the end of the lactation period, pups were
weaned and selected for the next generation or sacrificed. F0-and
F1-dams were sacrificed
at or shortly after weaning. F0- and F1- males were sacrificed after
at least 11weeks
of exposure (for sperm analyses and necropsy).
following effects were considered as treatment related and consistent
parental effects: increased relative thyroid weight in the F0- and
F1-males of the mid-dose group, increased thyroid weight of the F0-and
F1-animals of the high-dose group,increased liver weight of the F0-
and F1-animals of the high-dose group and decreased spleen weight in
the F0- and F1-animals of the high-dose groups.
periportal hepatocellular hypertrophy in the liver of the F0-animals
of the high-group was considered to be a treatment-related effect.
Activated/diffuse hypertrophy was observed in the thyroid in 0, 3, 6
and 10 male animals of the control, low-, mid- and high dose,
respectively. In the females this effect on the thyroid was only
observed in the animals of the high-dose group. The effect on the
thyroid in the male animals of the low-dose group did not reach the
level of significance. No reproductive toxicity was observed in this
study. There was no developmental toxicity, but systemic toxicity to
the offspring in the high-dose groups due to direct intake of the test
substance, decreased body weight and numbers of runts at the end of
the lactation period in the high dose F1 and F2 pups and decreased
relative spleen weight in F2-pups of the high dose group.
The NOAEL for parental toxicity of the
test substance is 29 mg/kg bw/day for male rats and 97 mg/kg bw/day
for female rats based on the histopathological changes in the liver
The NOAEL for toxicity to offspring and
developmental toxicity of 29 mg/kg was derived in the EU risk
assessment. This was based on an increase in the number of runts on PN
1 and a decrease in mean pup weights observed in the mid and high dose
groups of both generations. However,
as indicated in the original study report, the effects on PN1
are likely a statistical artefact of the study and not biologically
relevant for the following reasons: In this particular study the body
weights of the control animals were at the high end or even higher
than recent historical control body weights of the test institute and
are in a relatively narrow range with a comparatively low standard
deviation. Therefore the statistical evaluation overestimates the
effects identifying more animals as runts. When related to historical
control data in the F0 generation all mean body weights of the low and
high dose group are within the historical control range. Furthermore,
when compared on a litter basis the effects on body weights of the
pups on day 1 are not statistically significant in the F0 and F1
generation except for the F0 mid dose group. When looking at single
animal data, runts on day 1 stem from mother animals with considerably
lower body weights compared to the means of the respective groups and
the effects on body weights are likely related to maternal toxicity.
The increase in the number of runts as well as the decrease in pup
weight in the high dose group towards the end of the lactation period
is considered as toxicity to the offspring. Rather the reduced food
intake (reduced palatability) is considered to be the cause for the
retarded growth during the last week of lactation. Therefore the
original study report only considered reduced body weights and numbers
of runts at the end of the lactation period in the high dose group as
substance related effects in this study. These effects are due to
direct substance intake of the pups via the feed and are not
considered as developmental toxicity. Therefore it can be concluded
that in this study the substance did not show developmental toxicity.
Direct toxicity via substance intake of the pups from the diet was
seen at the high dose and the NOAEL for direct toxicity to the
offspring can be considered the mid dose of 97 mg/kg bw.
study is conducted according to GLP and satisfies
requirement for a 2
-generation reproductive study according to OECD Guideline No.416. The
study is considered as reliable without restrictions.
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