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EC number: 257-077-0
CAS number: 51240-95-0
For all tables:
N = No animals = 10 unless indicated
Group 1 = Control; Group 2 = 10 mg/kg bw/day; Group 3 = 100 mg/kg
bw/day; Group 4 = 300 mg/kg bw/day
* Significantly different from control group p<0.05
** Significantly different from control group p<0.01
*** Significantly different from control group p<0.001
n Data not appropriate for statistical analysis
Table 1 Group Mean Hematological Values
Table 2 Group Mean Blood Chemical Values
Table 3 Group Mean Organ Weights
Table 4 Sperm Concentration and Motility - Group Mean Values
Table 5 Sperm Morphology - Group Mean Values
Table 6 Homogenisation Resistant Spermatid Counts - Group Mean Values
The study was designed to investigate the
systemic toxicity of the test item and is compatible with the following
i) The OECD Guidelines for Testing of
Chemicals No. 408 "Repeated Dose 90-Day Oral Toxicity Study in Rodents”
(Adopted 21 September 1998).
This study was also designed to be
compatible with 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 by gavage to
three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST
strain rats, for ninety consecutive days, at dose levels of 10, 100 or
300 mg/kg bw/day. A control group of ten males and ten females was dosed
with vehicle alone (Arachis oil BP). Two recovery groups, each of ten
males and ten females, were treated with the high dose (300 mg/kg
bw/day) or the vehicle alone for ninety consecutive days and then
maintained without treatment for a further twenty-eight days.
Clinical signs, functional observations,
body weight change, dietary intake and water consumption were monitored
during the study. Hematology and blood chemistry were evaluated for all
non-recovery group animals at the end of the treatment period and for
all recovery group animals at the end of the treatment-free period.
Urinalysis was performed for all non-recovery and recovery animals
towards the end of the treatment and treatment-free periods,
respectively. Ophthalmoscopic examination was also performed on
non-recovery control group and non-recovery high dose animals.
All animals were subjected to gross necropsy
examination and histopathological evaluation of selected tissues from
all non-recovery control and high dose animals as well as any gross
lesions was performed in the first instance. As there were
treatment-related findings in the kidneys (males only), the liver and
the thyroid gland (males and females), examination of these tissues was
subsequently extended to include relevant animals from the remaining
dose groups on the study.
Where appropriate, quantitative data was
subjected to statistical analysis to detect the significance of
intergroup differences from control; statistical significance was
achieved at a level of p<0.05. Statistical analysis was performed on the
Grip Strength, Motor Activity, Body Weight
Change, Hematology, Blood Chemistry, Urinalysis (Volume and Specific
Gravity), Absolute Organ Weights, Body Weight-Relative Organ Weights.
Data were analyzed using the decision tree
from the ProvantisTM Tables and Statistics Module as detailed as follows:
The homogeneity of variance from mean values
was analyzed using Bartlett’s test.
Intergroup variances were assessed using
suitable ANOVA or ANCOVA with appropriate covariates. Any transformed
data were analyzed to find the lowest treatment level that showed a
significant effect using the Williams Test for parametric data or the
Shirley Test for non-parametric data. If no dose response was found but
the data shows nonhomogeneity of means, the data were analyzed by a
stepwise Dunnett’s (parametric) or Steel (non-parametric) test to
determine significant difference from the control group. Where the data
were unsuitable for these analyses, pair-wise tests was performed using
the Student t-test (parametric) or the Mann-Whitney U test
(non-parametric). Urine volume and specific gravity as well as sperm
analysis parameters were statistically analyzed using the R Environment
for Statistical Computing. Distribution of the data was assessed by the
Shapiro-Wilk normality test, followed by assessment of the homogeneity
of the data using Bartlett’s test. Where considered appropriate,
parametric analysis of the data was applied incorporating analysis of
variance (ANOVA), which if significant, was followed by pairwise
comparisons using Dunnett’s test. Where parametric analysis of the data
was unsuitable, non-parametric analysis was performed incorporating the
Kruskal- Wallis test followed by the Mann-Whitney "U" test.
There were no unscheduled deaths during the
Throughout the treatment period, there were
no clinical signs indicative of test item toxicity.
Behavioral assessment scores across the
test-item treated animals of either sex remained similar to the
Functional Performance Tests
There were no treatment-related changes in
functional performance for animals of both sexes at any dose level.
Sensory Reactivity Assessments
Sensory reactivity scores were comparable
across all dose groups including controls.
There was no adverse effect of treatment
with the test item at any dose level on body weight development in
animals of either sex.
There was no adverse effect of treatment
with the test item at any dose level on food consumption or food
conversion efficiency in animals of either sex.
When compared with controls, visual
inspection of water bottles did not reveal any intergroup differences in
animals of either sex receiving the test item.
Ophthalmoscopic examination of non-recovery
males and females from the control and 300 mg/kg bw/day dose groups
during Week 12 of the study did not reveal any treatmentrelated
There was no adverse effect of treatment
with the test item at any dose level on the nature of estrous cycle with
most females showing regular cycles over the last three weeks of dosing.
Hematology evaluations at the end of the
treatment or treatment-free periods did not reveal any toxicologically
significant effects in animals of either sex resulting from treatment
with the test item.
Blood chemistry evaluations at the end of
the treatment or treatment-free periods did not indicate any effects of
toxicological relevance in animals of either sex resulting from test
Urinalysis evaluations towards the end of
the treatment or treatment-free periods did not identify any effects of
toxicological importance in males or females receiving the test item up
to a dose level of 300 mg/kg bw/day.
At the end of the treatment period, most
males from the 300 mg/kg bw/day dose group showed enlarged kidneys; 2/10
males had kidneys of mottled appearance. These findings correlated with
increased kidneys weights and a perceived α-2u-globulin nephropathy
syndrome. At the end of the dose-free period, the macroscopic appearance
of the kidneys from males previously given 300 mg/kg bw/day was similar
There were no other macroscopic observations
at necropsy considered to be related to treatment with the test item.
Sperm evaluation at the end of the treatment
period identified reduced sperm concentration and motility which was
associated with an increase in sperm morphological abnormalities in
males treated with 100 or 300 mg/kg bw/day. These observations persisted
in some recovery males previously given 300 mg/kg bw/day after a
treatment-free period of twenty-eight days. Although microscopic
examination of the right testis or the right epididymis did not identify
any treatment-related alteration, the effect on sperm parameters was
considered to be of an adverse nature.
At the end of the dosing period, group mean
absolute and body weight-related left cauda epididymis weights in males
from the 300 mg/kg bw/day dose group were statistically significantly
lower than controls. This was no longer apparent in the recovery males.
Although there were no histopathology correlates, taken into
consideration the effect of treatment with the test item at a dose level
of 100 or 300 mg/kg bw/day on sperm concentration, motility and
morphology, the toxicological relevance of this finding was deemed
The increase in liver weights observed in
non-recovery males and females from the 300 mg/kg bw/day dose groups
showed complete reversibility in recovery animals and was considered to
be associated with adaptive microscopic alterations detected in the
livers from the non-recovery group animals. Increased kidneys weights in
non-recovery males from the 100 or 300 mg/kg bw/day dose groups which
persisted in the recovery males previously receiving 300 mg/kg bw/day
were considered to be associated with α-2u-globulin nephropathy syndrome.
Treatment-related findings were recorded in
the kidneys of males as well as the liver and thyroid gland of males and
females dosed with the test item. Some of the changes in the kidneys
persisted after the recovery period but all other changes had resolved.
The histopathology findings were as following:
At the end of the dosing period, hyaline
droplets were present in most males from all dose groups receiving the
test item. Multifocal basophilic tubules and proteinacious casts were
also observed in individual males given 10 mg/kg bw/day and most males
from the remaining dose groups. In addition, Lymphocytic infiltration
was present in 2/10 males from the 300 mg/kg bw/day dose group.
Immunohistochemical staining was positive for α-2u-globulin in males
from all groups with an indication of increased staining levels from
test item-treated animals.
At the end of the recovery phase, multifocal
basophilic tubules or multifocal nephropathy and proteinacious casts
were detected in all males previously receiving the test item at a dose
level of 300 mg/kg bw/day. Immunohistochemical staining was positive for
α-2u-globulin in all these males with levels similar in control and
Group 4 animals.
At the end of the dosing period, minimal
centrilobular hepatocyte hypertrophy was detected in a number of
individual males treated with 100 or 300 mg/kg bw/day (dose-related) and
most females receiving 300 mg/kg bw/day. At the end of the
treatment-free period, no findings related to the administration of the
test item were apparent in recovery animals of either sex.
At the end of the treatment period, minimal
hypertrophy of the follicular epithelium was observed in animals of
either sex receiving 100 or 300 mg/kg bw/day in a dose-related manner.
Changes in recovery males and females previously receiving 300 mg/kg
bw/day had resolved by the end of the treatment-free period.
The oral (gavage) administration of
1,1,3,3-tetramethylbutyl peroxyneodecanoate (CAS# 51240-95-0) to male
and female Wistar Han™:RccHan™:WIST strain rats at a dose level of 100
or 300 mg/kg bw/day resulted in toxicologically significant changes in
sperm concentration and motility and an associated increase in sperm
abnormalities. These were not reversible in males previously treated
with 300 mg/kg bw/day after a twenty-eight day treatment-free period. It
is therefore considered that a dose level of 10 mg/kg bw/day could be
established as a No Observed Adverse Effect Level (NOAEL) for systemic
toxicity in the
male within the confines of this type of
study. In contrast, there were no changes of toxicological significance
in the females up to a dose level of 300 mg/kg bw/day, which could
therefore be established as a NOAEL in the female within the confines of
this type of study.
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