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EC number: 947-957-9
CAS number: -
In total eight females from control, nine females from the 60 mg/kg
bw/day dose group and ten females from the 125 and 250 mg/kg bw/day dose
group gave birth to a live litter and successfully reared young to Day 5
age. The following assessment of litter response is based on all litters
reared to termination on Day 5 of lactation/age.
OFFSPRING LITTER SIZE AND VIABILITY
No toxicologically significant effects were detected.
No significant differences were detected for corpora lutea, implantation
counts, litter size or litter viability for treated animals when
compared to controls. Statistical analysis of the data did not reveal
any significant intergroup differences.
There were no intergroup differences in sex ratio (percentage male
offspring) for litters from treated groups compared to controls.
Statistical analysis of the data did not reveal any significant
OFFSPRING GROWTH AND DEVELOPMENT
There were no significant differences in litter, offspring weights or
surface righting reflex. Statistical analysis of the data did not reveal
any significant intergroup differences.
No obvious clinical signs of toxicity were detected for offspring from
treated females when compared to controls. The incidental clinical signs
detected throughout the control and treated groups, consisting of small
size, offspring found dead or missing, no milk in stomach, cold, weak,
pale, no tail and physical injury were considered to be low incidence
findings observed in offspring in studies of this type, and were
unrelated to test item toxicity.
No treatment-related macroscopic abnormalities were detected for interim
death or terminal kill offspring. The incidental findings observed were
those occasionally observed in reproductive studies of this type and
were considered to be unrelated to toxicity of the test item.
The study was designed to investigate the systemic toxicity and
potential adverse effects of the test item on reproduction (including
offspring development) and are compatible with the requirements of the
OECD TG 422.
This study was also designed to be compatible with the Commission
Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods
pursuant to Regulation (EC) No 1907/2006 of the European Parliament and
of the Council on the Registration, Evaluation, Authorisation and
Restriction of Chemicals (REACH).
The test item was administered twice daily by gavage to three groups,
each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats,
for up to eight weeks (including a two week maturation phase, pairing,
gestation and early lactation for females), at dose levels of 0, 60, 125
and 250 mg/kg bw/day. A control group of ten males and ten females was
dosed with vehicle alone (Arachis oil BP).
Clinical signs, behavioural assessments, body weight change, food and
water consumption were monitored during the study.
Pairing of animals within each dose group was undertaken on a one male:
one female basis within each treatment group on Day 15 of the study,
with females subsequently being allowed to litter and rear their
offspring to Day 5 of lactation.
During the lactation phase, daily clinical observations were performed
on all surviving offspring, together with litter size and offspring
weights and assessment of surface righting reflex.
Extensive functional observations were performed on five selected males
from each dose group after the completion of the mating phase, and for
five selected parental females from each dose group on Day 4
post-partum. Haematology and blood chemistry were evaluated prior to
termination on five selected males and females from each dose group.
Adult males were terminated on Day 43, followed by the termination of
all females and offspring on Day 5 post-partum. All animals were
subjected to a gross necropsy examination and histopathological
evaluation of selected tissues was performed.
Mortality: There were no unscheduled deaths.
Episodes of increased salivation were evident in animals of either sex
treated with 250 mg/kg bw/day and in males treated with 125 mg/kg bw/day
during the treatment period. An isolated incident of noisy respiration
was also evident in one female treated with 250 mg/kg bw/day on Day 6.
No such effects were detected in females treated with 125 mg/kg bw/day
or animals of either sex treated with 60 mg/kg bw/day. Such effects on
salivation are likely due to the palatability of the test substance
which is a known skin irritant.
There were no toxicologically significant changes in the behavioural
Functional Performance Tests.
There were no toxicologically significant changes in functional
Sensory Reactivity Assessments.
There were no treatment-related changes in sensory reactivity.
Males treated with 250 mg/kg bw/day showed a reduction in body weight
gain during Weeks 1, 2 and during the final week of treatment. No such
effects were detected in females treated with 250 mg/kg bw/day or
animals of either sex treated with 125 or 60 mg/kg bw/day.
Males treated with 250 mg/kg bw/day showed a slight reduction in overall
food consumption when compared to controls. No such effects were
detected in females treated with 250 mg/kg bw/day or in animals of
either sex treated with 125 or 60 mg/kg bw/day.
No toxicologically significant effect on water consumption was detected.
Mating and Fertility: There were no treatment-related effects on mating
or conception rates for treated animals.
There were no treatment-related differences in gestation lengths. The
distribution for treated females was comparable to controls.
Offspring Litter Size and Viability: Of the litters born, litter size at
birth and subsequently on Day 1 and 4 post-partum were comparable to
controls. There were no significant intergroup differences in sex ratio.
Offspring Growth and Development.
Offspring bodyweight gain and litter weights at birth and subsequently
on Day 1 and 4 post-partum were comparable to controls.
No clinically observable signs of toxicity were detected for offspring
from all treatment groups.
Haematology: There were no toxicologically significant effects detected
in the haematological parameters examined.
Blood Chemistry: There were no toxicologically significant effects
detected in the blood chemical parameters measured.
Necropsy: Sloughing on the non-glandular and/or glandular regions of the
stomach were evident in a number of animals treated with 250 and 125
mg/kg bw/day and in one male treated with 60 mg/kg bw/day. No such
effects were detected in females treated with 60 mg/kg bw/day.
No toxicologically significant effects were detected in the organ
Stomach: Focal to multifocal squamous hyperplasia with hyperkeratosis,
submucosal inflammation, and sometimes erosion in the forestomach were
noted in a dose-related manner in treated animals of all dose groups.
The minimally increased incidence of mucosal glandular dilation in the
glandular stomach of females from intermediate and high dose groups were
considered secondary to the locally irritant effects in the forestomach.
The oral administration of Reaction mass of bis(2-ethylhexyl) hydrogen
phosphate and 2-ethylhexyl dihydrogen phosphate to rats by gavage, at
dose levels of 0, 60, 125 and 250 mg/kg bw/day, resulted in some effects
in animals of either sex from all treatment groups, none of which were
considered to be due to adverse systemic toxicity. The histopathological
changes seen in the forestomach may be a result of local irritation of
the test item rather than a true effect of systemic toxicity. The NOAEL
for systemic toxicity was therefore determined to be 250 mg/kg bw/day.
Additionally, no treatment related effects were detected in any of the
reproductive parameters examined and therefore the NOEL for
reproductive/developmental toxicity was greater than 250 mg/kg bw/day.
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