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EC number: 218-664-7
CAS number: 2212-81-9
For 2212 -81 -9 an OECD 422 is available.
Form this study the parental NOAEL is 300 mg/kg bw/day, based on adverse
effects on the liver (i.e. hepatocellular necrosis and substantial liver
enlargement) and kidneys (i.e. tubular degeneration) at 1000 mg/kg
bw/day in both sexes. The key NOAEL for repeated dose toxicity study in
the read-across substance 25155 -25 -3, was established at 200 mg/kg/day
in males and females rats considering the adverse effects observed at
800 mg/kg/day on the body weight gain in males and the kidneys in males
and females during a 90-day study.
For further details on the read across
rationale see section 13.2.
The concentrations analyzed in the
formulations of Groups 2, 3 and 4 were in agreement with the target
concentrations (mean accuracies between 96.2% and 98.7%). No test item
was detected in the Group 1 formulation.
The formulations of Groups 2 and 4 were
homogeneous (coefficient of variation of 2.8% and 2.1% in the low and
high dose goups, respectively).
Text Table 1
Mean Percent Organ Weight Differences from Control Groups
Dose level (mg/kg):
Relative to body weight
**: P<0.01. - no
2. Summary Test Item-Related Microscopic Findings – Scheduled Euthanasia
a = Number
of tissues examined from each group.
Hyaline droplet accumulation
Follicular cell hypertrophy
a = Number
of tissues examined from each group.
In an OECD 422 study, Wistar Han rats were
treated with 1,3-bis(tert-butylperoxyisopropyl)benzene by daily oral
gavage at dose levels of 100, 300 and 1000 mg/kg bw/day (10
rats/sex/dose level). Concurrent
controls (10 rats/sex) 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 14 or16 days of lactation (for 50-56 days).
Females without offspring were treated for 41 days (two non-pregnant
Formulation analysis showed that the
formulations were prepared accurately and homogeneously.
Exposure to the test item resulted in
adverse changes in the liver and kidneys at 1000 mg/kg bw/day and a
variety of non-adverse changes, starting at 100 mg/kg bw/day, as
One female at 1000 mg/kg bw/day died
prematurely, while in labour, most likely due to test itemrelated
hepatotoxicity (i.e. moderate centrilobular hepatocellular necrosis).
Several males and females treated at 1000 mg/kg bw/day showed
piloerection after about one or two weeks of treatment. As the
piloerection was not observed continuously and occurred in absence of
other clinical signs of toxicity, it was considered not to reflect
general ill health. Slight salivation observed after dosing among
treated animals (at all dose levels) was considered a physiological
response rather than a sign of systemic toxicity.
Male rats treated at 1000 mg/kg bw/day
showed reduced body weight gain throughout treatment, accompanied by
reduced food consumption mainly in the first two weeks, with slight
weight loss in several animals in the last treatment week. To a lesser
extent, reduced weight gain also occurred in males at 300 mg/kg bw/day
(without a decrease in food consumption). As the resulting decreases in
mean body weights were modest (less than 10% at the end of the treatment
period), the effect on body weight (gain) was regarded as non-adverse
within the context of this study.
Functional observation tests showed reduced
motor activity in all females at 1000 mg/kg bw/day. For 3/5 females the
numbers of total movements and ambulations were below the historical
control ranges. There were no corroborative changes in other functional
measures in the neuromuscular domain (including grip strength, gait and
air righting reflex), supportive morphological correlates in examined
neuronal tissues, or related clinical signs. Therefore, the lower motor
activity in 1000 mg/kg bw/day females was considered not to reflect
impaired neuromuscular function and was regarded as non-adverse within
the context of this study.
Microscopic examination revealed test
item-related changes in several organs as described below.
At 1000 mg/kg bw/day, test item-related
renal toxicity was indicated by the presence of tubular degeneration in
the kidneys of several males (1/5 slight, 2/5 moderate) and females (2/5
minimal). The increased plasma level of creatinine in males was likely
related to the renal toxicity. Additional microscopic renal findings
consisted of increases in the incidence and/or severity of tubular
basophilia at 300 mg/kg bw/day in males (2/5 minimal, 2/5 slight) and
1000 mg/kg bw/day in males (3/5 slight) and females (2/5 minimal, 1/5
slight), hyaline droplet accumulation in males at 300 mg/kg bw/day (1/5
slight, 4/5 moderate) and at 1000 mg/kg bw/day (3/5 slight, 2/5
moderate), and tubular mineralization in females at 300 mg/kg bw/day
(2/5 minimal, 1/5 slight, 1/5 moderate) increases in relative renal
weights at 300 mg/kg bw/day in males and at 1000 mg/kg bw/day in both
The renal findings at 300 mg/kg bw/day were
regarded as non-adverse since they were not associated with degenerative
Hepatocellular necrosis was observed in the
liver of one 1000 mg/kg bw/day male (at slight degree) and one 1000
mg/kg bw/day female (at moderate degree; this female died prematurely).
This necrosis was considered an adverse change. Additional microscopic
changes in the liver consisted of centrilobular hepatocellular
hypertrophy in males at 100 mg/kg bw/day (3/5 minimal, 1/5 slight), at
300 mg/kg bw/day (4/7 minimal, 1/7 slight), at 1000 mg/kg bw/day (1/10
minimal, 8/10 slight) and in females at 1000 mg/kg bw/day (2/5 minimal,
3/5 slight), and pigment deposition in the liver in males at 300 mg/kg
bw/day (1/7 minimal, 1/7 slight) and at 1000 mg/kg bw/day (2/10
minimal). The hepatocellular hypertrophy correlated with enlargement of
the liver and the pigment deposition sometimes correlated with
macroscopic black-brown discoloration. Some changes in clinical
biochemistry parameters noted in 1000 mg/kg bw/day males may be related
to the effect on the liver (higher alanine aminotransferase (ALAT)
activity and lower cholesterol). The hepatocellular hypertrophy at 1000
mg/kg bw/day was associated with a degenerative change (hepatocellular
necrosis) and therefore considered part of a group of effects indicating
adversity. Furthermore, the magnitude of the liver enlargement at 1000
mg/kg bw/day (males had about 80% higher relative liver weights) was
considered to exceed thresholds for adversity. The hepatic changes
observed at 100 and 300 mg/kg bw/day were considered to be non-adverse
as they occurred in the absence of any degenerative or inflammatory
Microscopic changes in the thyroid gland
included an increased incidence and/or severity of follicular cell
hypertrophy in males at 100 mg/kg bw/day (1/5 minimal, 3/5 slight), at
300 mg/kg (2/5 minimal, 3/5 slight), at 1000 mg/kg (1/6 minimal, 5/6
slight) and in females at 300 mg/kg (1/5 minimal, 4/5 slight) and at
1000 mg/kg (2/5 slight, 3/5 moderate), and the presence of colloid
alteration at 1000 mg/kg w/day in males (1/6 minimal) and females (4/5
minimal). This was associated with higher thyroid weights at 300 in
males and 1000 mg/kg bw/day in both sexes. As these findings occurred in
the absence of any degenerative change in the thyroid they were regarded
as non-adverse. While increased follicular cell hypertrophy occurred in
both sexes, serum levels of thyroid hormones were affected only in
males. Starting at 300 mg/kg bw/day, serum levels of T4 were decreased
dose-dependently (about 50% at 1000 mg/kg bw/day) and TSH levels were
increased (on average nearly 10-fold at 1000 mg/kg bw/day). A decrease
in T4, with increases in TSH and thyroid follicular cell hypertrophy and
growth as compensatory responses, may be due to increased T4 turnover
resulting from metabolic enzyme induction in the liver (hepatocellular
Lymphoid atrophy in the thymus was observed
in males at 1000 mg/kg bw/day (3/5 minimal). Based on its minimal
severity, the lymphoid atrophy was regarded as non-adverse. It
correlated with a decrease (of about 40%) in the weight of the thymus.
The smaller decrease in thymus weight noted in 300 mg/kg bw/day males
was not associated with microscopic changes, and therefore not regarded
Clinical chemistry results showed changes in
some liver- or kidney-related parameters in 1000 mg/kg bw/day males (see
above). Additional changes, all in males, consisted of higher plasma
levels of total protein and potassium starting at 300 mg/kg bw/day and
higher albumin at 1000 mg/kg bw/day.
Although these changes could not be related
to adverse anatomic pathology findings, they were considered to be
toxicologically relevant based on their magnitude (mean values in
treated males exceeded historical control ranges).
Haematology showed a few changes in red
blood cell parameters at 1000 mg/kg bw/day: lower haemoglobin
concentration in males, and lower mean corpuscular volume (MCV) and mean
corpuscular haemoglobin (MCH) in females. As these changes were slight
(less than 10% difference from control values) they would not impact
tissue oxygenation and were, therefore, regarded as non-adverse.
Based on the results of this combined 28-day
repeated dose toxicity study with the reproduction/developmental
toxicity screening test, the following No Observed Adverse Effect Level
(NOAELs) of 1,3-bis(tert-butylperoxyisopropyl)benzene were established:
Parental NOAEL: 300 mg/kg bw/day, based on
adverse effects on the liver (i.e. hepatocellular necrosis and
substantial liver enlargement) and kidneys (i.e. tubular degeneration)
at 1000 mg/kg bw/day in both sexes.
Note: In this study, significant
treatment-related changes in serum levels of total T4 (decreased) and
TSH (increased) were observed at 300 and 1000 mg/kg bw/day (in males
only). However, possible adversity of this effect could not be assessed
within this type of screening study and was therefore not taken into
account when determining the parental NOAEL.
Table 5 Incidence and Severity of Noteworthy Microscopic
Findings in the Kidneys at Terminal Kill
Dose (mg/kg bw/day)
Number of animals
Hyaline droplets, tubular epithelium
Tubular basophilia, focal/multifocal
Cytoplasmic pigmented vacuoles, tubular epithelium
examined; - : no animal affected
*: Mean severity is ∑ number of animals x severity / number of
examined organs in the group
Table 6 Incidence and Severity of Noteworthy Microscopic
Findings in the Kidneys at Recovery Kill
Table 7 Incidence and Severity of Noteworthy Microscopic
Findings in the Liver at Terminal Kill
Table 8 Incidence and Severity of Noteworthy Microscopic
Findings in the Thyroid at Terminal Kill
Hypertrophy, follicular cell
Table 9 Incidence and Severity of Noteworthy Microscopic
Findings in the Thyroid at Recovery Kill
*: Mean severity is ∑ number of animals x severity / number of
examined organs in the group
In a subchronic toxicity study
performed according to the OECD test guideline no. 408 and GLP, Luperox
F (96.7% of 2,2-Bis(t-butylperoxy isopropyl)benzene) was administered
daily by oral gavage to-bred Wistar rats of both sexes at dose levels of
50, 200 and 800 mg/kg body weight/day for a period of 91/92 days. A
control group was treated similarly with the vehicle, corn oil, only.
The groups comprised 10 animals per sex which were sacrificed after
91/92 days of treatment. Additional 5 rats per sex and group were used
at 0 and 800 mg/kg. These animals were treated for 91 days and then
allowed a 28-day treatment-free recovery period after which they were
sacrificed. Clinical signs, detailed cage observation, food consumption
and body weights were recorded periodically during the acclimatization,
treatment and recovery periods. Functional observational battery,
locomotor activity and grip strength were performed during week 13. At
the end of the dosing and the treatment-free recovery period, blood
samples were withdrawn for hematology and plasma chemistry analyses.
Urine samples were collected for urinalyses. All animals were killed,
necropsied and examined post mortem. Sperm analysis was performed in all
males. Histological examinations were performed on organs and tissues
from all control and high dose animals, and all gross lesions from all
animals. Due to test item-related morphologic changes in the kidneys,
stomach, thyroid, spleen, and liver of high-dose animals, these organs
from the mid- and low-dose group animals were examined.
No test item-related mortalities were
recorded. Salivation was observed at all dose levels after the
administration. The incidence and frequency of salivation increased with
the dose level. No effects on behavior or reflexes were observed at any
dose level. No effects on grip strength were observed. No effects of the
treatment with the test item on locomotor activity were recorded. In
group 4, slightly lower absolute food consumption was recorded in males.
Slightly increased food consumption was recorded in females of group 4.
During the recovery period, the food consumption of group 4 males and
females was similar to the controls. No effects on food consumption were
recorded in animals of groups 2 and 3. In group 4, decreased body
weights and lower body weight gain were recorded in males from treatment
week 2 onwards. At the end of the recovery period, the mean body weights
of group 4 males where still slightly lower than in the control group.
In group 3, slightly decreased body weights were recorded in males from
treatment week 7 onwards. No effects on body weight development were
recorded in males of group 2 and in females at any dose level. No
effects of the treatment were recorded at ophthalmoscopic examinations.
In group 4, signs of slight regenerative anemia which included decreased
erythrocyte count, decreased hemoglobin concentration, decreased
hematocrit, and an increase of immature red blood cells were recorded.
In addition, platelet counts were increased in both sexes of group 4.
Slightly prolonged prothrombin time and shortened activated partial
thromboplastin time was recorded in females of groups 3 and 4. All these
changes were not considered as adverse, because they were of low
magnitude and not observed at the end of the recovery period. Total
protein, albumin and/or globulin concentration was slightly increased in
females at all dose levels and in males of group 4. Cholesterol and
phospholipide concentration was increased in females of groups 3 and 4.
In addition, the triglyceride concentration was increased in females of
group 4. A decrease of the glucose concentration together with an
increase of the urea concentration was recorded in males of group 4. All
these changes were not considered as adverse, because they were of low
magnitude and not observed at the end of the recovery period. In group
4, increased ketone concentrations were recorded in urines of males.
These changes were reversible, because they were not observed at the end
of the recovery period. A dose-related increase of liver weights was
recorded in males of groups 3 and 4 and in females at all dose levels.
Kidney weights were increased in males of groups 3 and 4. No effects of
the treatment with the test item on sperm motility, morphology and sperm
counts were observed. No macroscopic findings related to the treatment
with the test item were observed. In the kidneys, hyaline droplets
immunostained by an anti alpha 2µ-globulin antibody were recorded in the
proximal tubules of males at all dose levels with a dose-related
increase of the mean severity. Karyomegaly, tubular basophilia and
pigmented vacuoles in the proximal tubules of the kidneys of males and
females were recorded in group 4, mean severity being higher in males.
Hyaline droplets in the tubular epithelium, karyomegaly,
focal/multifocal tubular basophilia and cytoplasmic pigmented vacuoles
in tubular epithelium were still observed at the end of the recovery
period; however, incidence and/or severity of the findings were lower
when compared to the end of the treatment period. Liver adaptive
hepatocellular hypertrophy was recorded in males and females of groups 3
and 4 with a dose-related increase of the mean severity. In animals of
the recovery group there were no test-item related findings in the
liver. Thyroid follicular cell hypertrophy secondary to the liver enzyme
induction was recorded with a dose-related increase of the mean severity
in males at all dose levels and in females of groups 3 and 4. Minimal to
slight follicular cell hypertrophy was also observed in males and
females of the recovery group. In the spleen, increased extramedullary
hematopoiesis secondary to increased red blood cell turn over was
recorded in males of groups 3 and 4 and in females of group 4, and
increased hemosiderosis in females of group 4. Minimal increased
hemosiderosis was still present in 2 out of 5 recovery females of group
4. Erosion/ulcer of the non-glandular stomach was recorded in females of
group 4. In animals of the recovery group there were no test-item
related findings in the stomach.
Based on the results of this study,
the NOAEL in males and females rats was established at 200 mg/kg/day
considering the adverse effects observed at 800 mg/kg/day on the body
weight gain in males and the kidneys in males and females.
According to regulation (CE) n°1272/2008,
[1,3 -phenylenebis(1 -methylethylidene)]bis[tert-butyl] peroxide is not
classified as toxic in case of repeated exposure as evidenced by the
test results of structurally analogous 2,2 -Bis(t-butylperoxy isopropyl)
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