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EC number: 235-935-5
CAS number: 13052-09-0
There were no toxicologically
significant effects detected in sperm motility values, morphological
assessments or in homogenisation-resistant spermatid counts for males
receiving 1000 mg/kg bw/day.
study was designed to investigate the systemic toxicity and potential
adverse effects of the test item on reproduction (including offspring
development) and is compatible with the requirements of the OECD
Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose
Toxicity Study with the Reproduction/Developmental Toxicity Screening
Test” (adopted 22 March 1996).
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).
test item was administered by gavage to three groups, each of ten male
and ten female Wistar Han™:RccHan™:WIST strain rats, for up to sixteen
weeks (including an eleven week pre-pairing phase, pairing, gestation
and early lactation for females), at dose levels of 30, 300 and 1000
mg/kg bw/day. A control group of ten males and ten females was dosed
with vehicle alone (Arachis oil BP).
signs, behavioural assessments, body weight change, food and water
consumption, oestrous cycles and opthalmic change were monitored during
animals within each dose group was undertaken on a one male: one female
basis within each treatment group on Day 78 of the study, with females
subsequently being allowed to litter and rear their offspring to Day 5
lactation phase, daily clinical observations were performed on all
surviving offspring, together with assessments of litter size, offspring
weights and surface righting reflex.
Extensive functional observations were
performed on males from each dose group during Week 15 and for parental
females from each dose group on Day 4post partum. Haematology
and blood chemistry were evaluated prior to termination on males
(Day 110) and females (Day 4 of lactation) from each dose group. An
opthalmic examination was made for control and high dose animals prior
to treatment and during Week 13 for females and Week 15 for males.
Adult males were terminated on Day
112, followed by the termination of all surviving females and offspring
on Day 5post partum. Any female which did not produce a pregnancy
was terminated on or after Day 25post coitum. All animals were
subjected to a gross necropsy examination with recording of selected
organ weight and additionally sperm analysis for males.
Histopathological evaluation of selected tissues was performed, with
enhanced assessment of testes for males.
1000 mg/kg bw/day, one female was found dead on Study Day 98 (Day 18 of
gestation) without any significant clinical signs being seen prior to
this event. Enlarged adrenals and a reddened left lung lobe were
apparent at necropsy but microscopic examination did not reveal the
aetiology of this death and this death was considered to be unrelated to
signs associated with treatment were confined to increased post dosing
salivation for both sexes at 1000 mg/kg bw/day, and males and one female
at 300 mg/kg bw/day.
obvious neurological effects of treatment at 30, 300 or 1000 mg/kg
bw/day were apparent.
Functional Performance Tests.There
was no consistent pattern of results that indicated an effect of
treatment at 30, 300 or 1000 mg/kg bw/day.
Sensory Reactivity Assessments.Sensory
reactivity assessments to different stimuli did not reveal any effect of
treatment at 30, 300 or 1000 mg/kg bw/day.
was no adverse effect of treatment on body weight performance for males
or females, including during gestation and lactation phases at 30, 300
or 1000 mg/kg bw/day.
Food Consumption and Food
was no adverse effect of treatment on food consumption and food
conversion efficiency for males or females, including during gestation
and lactation phases, at 30, 300 or 1000 mg/kg bw/day.
1000 mg/kg bw/day, water consumption for males was slightly higher than
control throughout most of the study.
treatment-related effects were detected for animals at 1000 mg/kg bw/day.
was no adverse effect of treatment on female oestrous cycles at 30, 300
or 1000 mg/kg bw/day.
performance was unaffected by treatment at 30, 300 or 1000 mg/kg bw/day.
was unaffected by treatment at 30, 300 or 1000 mg/kg bw/day.
length was unaffected by treatment at 30, 300 or 1000 mg/kg bw/day.
Offspring Litter Size, Sex Ratio
and Viability.Corpora lutea
and implantation counts and subsequent post-natal litter size, sex ratio
and offspring survival were unaffected by treatment at 30, 300 and 1000
Offspring Growth and Development.Offspring
body weight, litter weight and surface righting ability on Day 1 and
subsequent clinical signs and offspring growth to Day 4 of age were
unaffected by treatment at 30, 300 and 1000 mg/kg bw/day.
treated with 1000 mg/kg bw/day showed increased platelet count compared
with control. No toxicologically significant effects were detected for
females at this dosage or either sex at 30 or 300 mg/kg bw/day.
at 1000 mg/kg bw/day showed increased total protein and albumin levels
compared to control. No similar effects were apparent for males at
1000 mg/kg bw/day or either sex at 30 or 300 mg/kg bw/day.
1000 mg/kg bw/day, two adult males showed mottled kidneys at necropsy
examination. There were no other necropsy findings for adult animals or
their offspring that were considered to be associated with treatment at
30, 300 or 1000 mg/kg bw/day.
both sexes at 1000 mg/kg bw/day and males at 300 mg/kg bw/day, absolute
and body weight relative kidney weights were statistically significantly
higher than control.
For males at 1000 mg/kg bw/day,
increased absolute and body weight relative liver weights also attained
statistical significance compared with control.
of sperm motility values, morphological assessments and
homogenisation-resistant spermatid counts for males at 1000 mg/kg bw/day
did not indicate any effects of treatment.
300 and 1000 mg/kg bw/day males showed adaptive liver changes consisting
of centrilobular hepatocellular hypertrophy; there were no degenerative
or inflammatory lesions.
At 300 and 1000 mg/kg bw/day males
also showed treatment related hyaline droplet nephropathy of the kidney,
consisting of increased incidence and severity of hyaline droplets,
tubular degeneration, granulated tubular casts and interstitial
For females at 30 mg/kg bw/day and
both sexes at 300 and 1000 mg/kg bw/day increased incidence and severity
of follicular hypertrophy was recorded in the thyroid. This finding was
considered to be a secondary effect of increased hepatic metabolism.
There were no abnormal lesions
encountered during testicular spermatogenesis staging for males at 1000
oral administration of
13052-09-0) to rats by gavage, at dose levels of 30, 300 and 1000 mg/kg
bw/day, resulted in treatment related findings in animals of either sex
treated with 30, 300 and 1000 mg/kg bw/day. The effects detected in
females were mainly confined to adaptive microscopic thyroid changes and
there were no findings observed that were considered to represent an
adverse effect of treatment. The ‘No Observed Adverse Effect Level'
(NOAEL) for females was considered to be 1000 mg/kg bw/day.
Kidney effects detected in males at
300 and 1000 mg/kg bw/day consisted of increased incidence and severity
of hyaline droplets, tubular degeneration, granulated tubular casts and
interstitial inflammatory infiltrate. This nephropathy was deemed to be
related to treatment and to represent an adverse effect of treatment to
the rat. Hyaline droplets were also present for males at 30 mg/kg bw/day
but, occurred in the absence of any degenerative changes and the ‘No
Observed Adverse Effect Level' (NOAEL) for males was therefore
considered to be 30 mg/kg bw/day. However, the kidney changes of hyaline
droplets were consistent with well documented changes that are peculiar
to the male rat in response to treatment with some hydrocarbons. This
effect is, therefore, not indicative of a hazard to human health. In the
context of this study, the remaining kidney findings, consisting of
tubular and/or degeneration, tubular dilation/vacuolation, granulated
tubular casts and interstitial inflammatory infiltrate detected in males
are more likely to be correlated to the same condition as hyaline
droplet accumulation and are, therefore, considered to represent limited
relevance to humans.
Effects excluding the kidney changes
detected in males were confined to adaptive microscopic liver and
thyroid changes. These were considered not to represent an adverse
effect of treatment. In terms of extrapolation to man and risk
assessment calculations whereby effects relating to male rat renal
changes are species and sex specific and therefore are not relevant, a
NOAEL for males can be established at 1000 mg/kg bw/day.
Enhanced evaluation of reproduction
for this study did not indicate any effect of treatment on reproduction
including litter size and offspring survival, growth and development at
dosages up to 1000 mg/kg bw/day. The ‘No Observed Effect Level’ (NOEL)
for reproductive toxicity was considered to be 1000 mg/kg bw/day.
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