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EC number: 256-032-2
CAS number: 42978-66-5
The various analyses confirmed
- Accuracy: The concentrations analyzed in the formulations
of Group 2, Group 3 and Group 4 were in agreement with target
concentrations (i.e. mean accuracies between 90% and 110%). No test item
was detected in the Group 1 formulation.
- Homogeneity: The formulations of Group 2 and Group 4 were homogeneous
(i.e. coefficient of variation ≤ 10%).
Table 6: Mean Percent Liver Weight Differences from
Dose level in mg/kg bw/d
Relative to bodyweight
P < 0.05, **: P < 0.01
7: Summary Test Item-Realted Microcopic Findings-(fore)stomach
Hyperplasia squamous cell
Number of tissues examined from each group
Table 8 Summary Test Item-Related Microscopic Findings – Liver and
Kidneys – Males
Hyaline droplet accumulation
Number of tissues examined from each group
Wistar Han rats were treated with the test
item by daily oral gavage at dose levels of 40, 125 and 375 mg/kg
according to OECD 422 and in compliance with GLP. The rats of the
control group received the vehicle, corn oil, alone. Males were treated
for 2 weeks prior to mating, during mating, and up to termination (for
29 days). Females that delivered offspring were treated for 2 weeks
prior to mating, during mating, during post-coitum, and at least 13-15
days of lactation (for 50-62 days). Females that failed to deliver pups
were treated for 40-53 days.
Parental toxicity was observed in the
(fore)stomach of males from 125 mg/kg and in females at 375 mg/kg.
These changes consisted of ulcers and
inflammation of the forestomach in males and hyperplasia squamous cells
in males and females.
Other treatment-related but non-adverse
changes were observed in the liver at microscopic examination. An
absolute increase of 31% and a relative increase of 25% in liver weight
was observed at dose 375 mg/kg. At microscopic examination,
hepatocellular hypertrophy in the liver was observed at minimal severity
and was in the absence of any indicators of cellular degeneration. The
changes in the liver were not considered adverse at current severities.
In the kidneys an increase in hyaline droplet accumulation was recorded
in males which was considered to likely represent alpha2uglobulin, a
normal protein in male rats which undergoes reabsorption in the proximal
cortical tubules (Alden et al., 1991). This male rat specific protein is
not present in female rats nor in higher mammals, including man (Sahota
et al., 2013). The increased hyaline droplet accumulation in the male
kidneys at 375 mg/kg/day was not accompanied by indicators of tubular
damage and therefore this was considered to be nonadverse.
Functional observations were not performed
for females and therefore, possible treatment related effects on the
functional parameters could not be evaluated.
No toxicologically significant changes were
noted in any of the remaining parameters investigated in this study
(i.e. clinical appearance, functional observations (males), body weight,
food consumption, clinical laboratory investigations (including male T4
thyroid hormone levels), macroscopic examination and organ weights).
Based on the results of this combined 28-day
repeated dose toxicity study with the reproduction/developmental
toxicity screening test, no systemic no-observed-adverse-effect level
(NOAEL) were established under the conditions of this study. The
Parental local NOAEL of 40 mg/kg is based on the findings in the
(fore)stomach. Due to the absence of systemic toxicity up to and
including the highest tested dose of 375 mg/kg bw/d no systemic NOAEL
could be derived.
Table 1 Developmental indeces
Dose in mg/kg bw/d
Post-implantation survival index (%)
Live birth index (%)
Viability index (%)
Lactation index (%)
Table 2 Developmental data
Total number of offspring born
Total number of uterine implantation sites
Number of live offspring on day 1 after littering
Number of live offspring on day 4 (before culling)
Number of live offspring on day 4 (after culling)
Number of live offspring on day 13 after littering
Wistar Han rats were treated with the test item by daily oral gavage at
dose levels of 40, 125 and 375 mg/kg according to OECD 422 and in
compliance with GLP. The rats of the control group received the vehicle,
corn oil, alone. Males were treated for 2 weeks prior to mating, during
mating, and up to termination (for 29 days). Females that delivered
offspring were treated for 2 weeks prior to mating, during mating,
during post-coitum, and at least 13-15 days of lactation (for 50-62
days). Females that failed to deliver pups were treated for 40-53 days.
The following developmental parameters were determined: Number of
implantation sites, gestation index and duration, parturition and
maternal care, live birth index, viability index and lactation index,
post-implantation survival index and early postnatal pup development
(mortality, clinical signs, body weights, sex, anogenital distance,
areola/nipple retention and macroscopy, measurement of thyroid hormone
T4 (PND 14-16 pups)).
Gestation index and duration of gestation were not considered to be
affected by treatment. Except for one female of the control group, all
pregnant females had live offspring. The gestation indices were 89% for
the control and 100% for the 40, 125 and 375 mg/kg groups, respectively.
No signs of difficult or prolonged parturition were noted among the
pregnant females. Examination of cage debris of pregnant females
revealed no signs of abortion or premature birth. No deficiencies in
maternal care were observed. The total number of offspring born compared
to the total number of uterine implantations was not considered to be
affected by treatment. Post-implantation survival index (total number of
offspring born as percentage of total number of uterine implantation
sites) was 92%, 79%, 88% and 85% for the control, 40, 125 and 375 mg/kg
groups, respectively. The slightly lower post-implantation survival
index for the 40 mg/kg group was considered the result of the low litter
size of female no. 51 which only had one pup, but 10 implantation sites.
The survival indices for all other groups were considered within normal
range. Litter size was not considered affected by treatment. Live litter
sizes were 10.9, 9.2, 12.1 and 11.6 living pups/litter for the control,
40, 125 and 375 mg/kg groups, respectively. Live birth index (number of
live offspring on PND 1 as percentage of total number of offspring born)
was considered not to be affected by treatment. The live birth indices
were 90%, 99%, 100% and 100% for the control, 40, 125 and 375 mg/kg
Eleven pups of the control group and one pup at 40 mg/kg were found dead
at first litter check. Eight of these pups were of the control group
female, which had a total litter loss. No toxicological relevance was
attributed to these dead pups since the mortality incidence mainly
occurred in the control group and did not show a dose-related trend.
Viability index (number of live offspring on PND 4 before culling as
percentage of number of live offspring on PND 1) was considered not to
be affected by treatment. Viability indices were 99%, 100%, 99% and 99%
for the control, 40, 125 and 375 mg/kg groups, respectively. Three
dead/missing pups were present throughout the study (one pub of the
control, 125 and 375 mg/kg bw/d expsoure group), however, the mortality
incidence did not show a dose-related trend and remained within the
range considered normal for pups of this age. The number of live
offspring on Day 13 after littering compared to the number of live
offspring on Day 4 (after culling) was not considered to be affected by
treatment. No pups were found dead/missing between lactation Days 5 and
13, resulting in a lactation index of 100% for all groups. The postnatal
pub deveopment was unaffected by the treatment.
Based on the results of this combined 28-day repeated dose toxicity
study with the reproduction/developmental toxicity screening test, no
developmental toxicity was observed up to and including the highest
tested dose of 375 mg/kg test item due to the abscence of respective
adverse effects under the conditions of this study.
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