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EC number: 254-179-7
CAS number: 38888-98-1
No toxicologically relevant effects on reproductive parameters were
noted. All paired females were mated, resulting in a mating index of
100% for treated and control groups. There were 10, 10, 10, and 8
pregnant females in the control, 10, 30, and 100 mg/kg bw/day groups,
respectively. Examination of the reproductive organs of the non-pregnant
females and their paired males did not reveal any abnormalities.
Assessment of the integrity of the spermatogenetic cycle did not provide
any evidence of impaired spermatogenesis. Therefore, the lower fertility
and conception indices for the high dose group was not regarded as
treatment related. Precoital time, and number of corpora lutea and
implantation sites were unaffected by treatment.
The gestation index and duration of gestation were unaffected by
treatment up to 100 mg/kg bw/day. There were only four females at 100
mg/kg bw/day with life offspring (8 pregnant females in total), the
gestation index for the high dose group was only 50%. Examination of the
reproductive organs of the nonpregnant females and their paired males
did not reveal any abnormalities. Assessment of the integrity of the
spermatogenetic cycle did not provide any evidence of impaired
spermatogenesis. Therefore, the incidence of two non-pregnant females in
the high dose group was not regarded as treatment related.
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 and no deficiencies in
maternal care were observed.
EARLY POSTNATAL PUP DEVELOPMENT
Treatment related effects on early postnatal pup development were noted.
The number of dead and living pups at first litter check, postnatal loss
and viability index were affected at 100 mg/kg bw/day:
- The average number of dead pups per litter at first litter check was
3.0 compared to 0.0 in the control group. - The average number of living
pups per litter at first litter check was 6.7 compared to 10.7 in the
- Postnatal loss comprised 18 pups of 5 litters compared to 1 pup of 1
litter in the control group.
- The viability index was 61.7% compared to 99.1% in the control group.
In addition, decreased body weights of pups (both sexes) were noted at
30 and 100 mg/kg bw/day.
At 100 mg/kg bw/day, in total 21 pups of 3 litters were found dead at
first litter check and 18 pups of 5 litters were found dead, killed in
extremis or missing during the first two days of lactation. In addition,
no pups were found for one female. This latter female had been pregnant
as indicated by the increased body weights and confirmed at necropsy by
the presence of 12 implantation sites in the uterus. No late resorptions
were found. Therefore, it is most likely that she had cannibalized her
litter shortly after delivery. In one litter only 2 out of 13 pups were
found alive at first litter check. Due to the bad condition of these two
pups (they were cold and had no milk in the stomach), they were
euthanized on lactation Day 1. Other pups (indicated as “missing”) were
lost by cannibalism during the lactation period. In total 4 litters were
lost completely. At the lower dose levels of 10 and 30 mg/kg bw/day, 1
pup/1 litter and 2 pups/2 litters, respectively, were found dead or
missing. In the control group, only one pup was missing. This occurrence
was within normal limits.
CLINICAL SIGNS PUPS
Clinical signs of pups found dead or missing consisted of little or no
milk in the stomach, and cold appearance. For one surviving control pup
a missing tiptoe on the right foot was noted from lactation Day 4
onwards. This finding was not related to treatment. Another pup at 30
mg/kg bw/day had a blue spot on the head from lactation Day 4 to Day 6.
This finding is more often seen for pups of this age. At the single
occurrence in this study and in the absence of a treatment-related
distribution, it was considered to be of no toxicological relevance.
BODY WEIGHT PUPS
Body weights were slightly lower for pups at 30 mg/kg bw/day (males
only) and 100 mg/kg bw/day (both sexes) as compared to control pups on
lactation Day 1. On Day 4 of lactation, body weights of treated and
control pups (both sexes) were within comparable ranges.
Absence of milk in the stomach was recorded for all dead pups, except
for three dead pups in one litter from group dosed to 100 mg/kg bw/day.
These latter dead pups could not be evaluated due to either severe
autolysis or cannibalism. No macroscopic abnormalities were noted for
the two pups that were killed in extremis. Incidental macroscopic
findings among surviving pups included the absence of milk in the
stomach. The nature and incidence of this finding remained within the
range considered normal for pups of this age, and was therefore
considered to be of no toxicological relevance.
A combined 28-day repeated dose toxicity study with the
reproduction/developmental toxicity screening test was conducted
according to OECD guidelines and GLP principles. Phenyl-tolyl-ethane was
administered by daily oral gavage to male and female Wistar Han rats at
dose levels of 10, 30 and 100 mg/kg bw/day. No significant and
toxicologically relevant changes in body weight gain were noted for any
of the groups. At 100 mg/ kg bw/ day, heamatological parameters
including increased red blood cells with corresponding slightly
increased haemoglobin and decreased reticulocytes with corresponding
decreased red blood cell distribution width (RDW), and decreased
platelets were noted in females, which correlated with decreased
hematopoietic foci in the spleen. Based on these data, the parental
NOAEL for PTE was established to be 30 mg/kg bw/ day. Mortality of the
pups occurred at 100 mg/kg bw day and reduced body weight of pups was
found at 30 and 100 mg/ kg bw/ day, therefore the NOAEL for Development
was established at 10 mg/ kg bw/ day.
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