Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 641-088-6
CAS number: 1229648-98-9
Table 1: Summary of clinical signs
Cold to the touch
Table 2: Summary of body weights and body
weight gains (in g)
Table 3: Mating data
Number of animals paired (M + F)
10 + 10
Number of males mated
Number of females mated
Mean number of days taken to mate
Table 4: Fertility data
Number of mated females
Number of pregnant females
Table 5: Delivery data
Mean duration of gestation (days)
Mean number ofcorpora lutea
Mean number of implantations
Mean pre-implantation loss (%)
Mean number of pups delivered
Mean post-implantation loss (%)(calculated manually)
Table 6: Pup body weight
Body weight (g)
Body weight change (g)
The objective of this study was to
evaluate the potential toxic effects of the test item following daily
oral administration (gavage) to male and female rats from before mating,
through mating and, for the females, through gestation until day 5 post-partum.
An additional satellite group was included in the control and high-dose
groups for observation of reversibility, persistence or delayed
occurrence of systemic/irritative effects for 4‑weeks post-treatment.
This study provides initial
information on possible toxicological effects likely to arise from
repeated exposure over a relatively limited period of time and on male
and female reproductive performance, such as gonadal function, mating
behavior, conception, development of the conceptus and parturition.
study was conducted according to OECD Guideline 422 and EPA guideline
OPPTS 870.3650 and
was in compliance with the principles of Good Laboratory Practice
Three groups of Sprague-Dawley rats
received the test substance daily, by gavage, before mating and through
mating and, for the females, through gestation until day 5post-partum.
The dose-levels were 5, 15 or 45 mg/kg bw/day. The low- and
intermediate-dose groups were each composed of 10 males and 10 females
and the high-dose group was composed of 15 males and 15 females. In the
high-dose group, the first 10 animals/sex having been mated were
sacrificed at the end of the treatment period ; the last 5 animals/sex
not mated were dosed for 4 weeks and then retained for a 4-week
Another group of 15 males and 15
females received the vehicle, sesame oil, alone, under the same
experimental conditions and acted as a control group. As for the
high-dose group, the first 10 animals/sex were mated and sacrificed at
the end of the treatment period and the last 5 animals/sex were retained
for a 4-week treatment-free period. The dosing volume was 5 mL/kg bw/day.
In all animals from the principal and
satellite groups, clinical signs and mortality were checked at least
once daily during the treatment period and detailed clinical
examinations were performed once before the beginning of the treatment
period and then once a week until the end of the study. Body weight and
food consumption were recorded weekly and at designated intervals
throughout gestation and lactation. A Functional Observation Battery,
including assessment of responses, reflexes, forelimb grip strength,
landing foot splay and rectal temperature, was performed on the first
five males and the first five females to deliver from each principal
group at the end of the study. At the end of the Functional Observation
Battery, motor activity was measured over a 1-hour period.
Blood and urine samples were taken
from the first five males and the first five females to deliver from
each principal group at the end of the treatment period for analysis of
hematology, blood biochemistry and urine parameters. In addition,
hematological and selected blood biochemical parameters were measured at
the end of the treatment-free period in the animals of the satellite
The first ten animals/sex/group were
paired for mating after 2 weeks of treatment and the females were
allowed to litter and rear their progeny until day 5post-partum.
The total litter sizes and numbers of pups of each sex were recorded
after birth. Pups were observed daily for clinical signs and pup body
weights were recorded on days 1 and 5 post-partum.
In the principal groups, males were
sacrificed after completion of the mating period and females on day 6 post-partum.
Animals from the satellite group were sacrificed at the end of the
treatment-free period. All animals were subjected to a complete
macroscopic post-mortem examination with a careful examination of
the stomach lining due to the strong irritant / corrosive properties of
the test item. A microscopic examination was performed on selected
organs of the first five males and the first five females to deliver
from the control and high-dose groups sacrificed at the end of the
treatment period, on the one non-pregnant female and on all macroscopic
lesions. In addition, the forestomach, ileum and mesenteric lymph nodes
from the low- and intermediate-dose groups sacrificed on completion of
the treatment period and from the control and high-dose groups
sacrificed at the end of the treatment-free period were examined.
Pups were sacrificed on post-natal
day 5 and were carefully examined for gross external abnormalities and
macroscopic abnormalities. Found dead and prematurely sacrificed pups
were also examined for gross external and macroscopic abnormalities.
There were no unscheduled mortalities.
Hypersalivation was observed in all males and females treated at 15 or
45 mg/kg bw/day. In addition, some males and females treated at 45 mg/kg
bw/day had loud breathing, round back, piloerection, hypoactivity and
half-closed eyes on occasions during the study. No relevant clinical
signs were observed at 5 mg/kg bw/day.
Males treated at 45 mg/kg bw/day had
statistically significantly lower mean body weight gains and food
consumption in the first week of treatment (seven males lost weight).
The deficit was not recouped during the treatment period or during the
treatment-free period. Females treated at 45 mg/kg bw/day also had
statistically significantly lower mean food consumption in the first
week of treatment.There were no effects at 5 or 15 mg/kg bw/day.
There were no effects on mating,
fertility or delivery at any dose-level. There were no increases in pup
mortality in the test item-treated groups and there were no relevant
clinical signs or gross abnormalities in the pups. Mean pup body weight
gain between post-natal days 1 and 5 at 45 mg/kg bw/ day was lower for
both sexes when compared with controls. There were no effects at 15 or
15 mg/kg bw/ day.
Laboratory investigations showed that
males treated at 45 mg/kg bw/day had a significant leucocytosis and a
slight anemia together with a decrease in protein and albumin
concentrations but at the end of the treatment-free period, all
parameters were comparable with controls. There were no
treatment-related effects on hematological and biochemical parameters at
5 or 15 mg/kg/day in males or in females at any dose-level.
No treatment-related effects on organ
weights and no particular macroscopic findings were observed.
Microscopic examination revealed
enlarged foamy macrophages graded as minimal or slight in the ileum of
males and females treated at 45 mg/kg bw/day. No particular findings
were found in the ileum of animals treated at 5 or 15 mg/kg bw/day.
Enlarged foamy macrophages, occasionally forming aggregates at high dose
and associated with dilation of sinuses, were also observed in the
mesenteric lymph nodes with a dose-related trend at all dose-levels in
females and from 15 mg/kg bw/day in males. At the lower doses, the
finding was marginal: 1 male treated at 15 mg/kg bw/day and 1 female
treated at 5 mg/kg bw/day had a minimal infiltration in the mesenteric
lymph nodes. As no degenerative changes were associated, this effect was
therefore considered to be non-adverse. Partial recovery was observed by
the end of the treatment-free period.
Symptoms related to the strong
irritant / corrosive nature of the test substance were observed in the
forestomach of males treated at 45 mg/kg bw/day at the end of the
treatment period. Males rats showed acanthosis and edema of the
forestomach mucosa and ulcerations and hyperplasia in the
forestomach.This was considered to be treatment-related and adverse. At
the end of the treatment-free period, only 1/5 males had minimal
acanthosis indicating recovery.
In conclusion, clinical signs of poor
condition were observed in some males and females at 45 mg/kg bw/day.
Week 1 body weight gain was markedly lower in males (some males lost
weight) and food consumption was reduced in males and females. Males did
At 5 and 15 mg/kg/day, there were no
adverse clinical signs and no effects on body weight or food
consumption. There were no effects on mating or fertility and there were
no effects on the pups after birth. None of the hematological or blood
biochemical parameters were affected by treatment and no abnormal
responses, reflexes or behavior were observed during the Functional
Observation Battery. There were no treatment-related macroscopic
findings and no treatment-related effects on organ weights.There were no
particular findings in the forestomach and ileum at microscopic
examination. Mesenteric lymph nodes revealed only minimal or slight
enlarged foamy macrophages in three females and one male treated at 15
mg/kg/day and in one female treated at 5 mg/kg/day.
Based on the experimental conditions
of this study, the
No Observed Adverse Effect Level (NOAEL) for parental toxicity with
respect to systemic toxic effects was considered to be 15 mg/kg/day
because of the reduction of body weight and body weight gain, the
significant changes in hematological and blood biochemical parameters
observed in males treated at 45 mg/kg/day.
The No Observed Effect Level (NOEL)
for reproductive performance (mating and fertility) was considered to be
45 mg/kg/day and the
No Observed Adverse Effect Level
(NOAEL) for toxic effects on progeny was 45 mg/kg bw/ day since the
lower body weight gain at this dose-level was only slight.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Do not show this message again