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EC number: 266-587-2
CAS number: 67151-63-7
Repeated dose toxicity - oral:
A GLP compliant 90-day repeated dose toxicity study according to OECD
guideline 408 was performed in rats via oral gavage. Dose levels tested
were 10, 25 and 75 mg/kg. The
NOEL for females was considered to be 25 mg/kg bw/day and 10 mg/kg
bw/day for males.
Repeated dose toxicity - dermal/inhalation: No reliable data were
available for these exposure routes. Therefore, no NOAEL for these
routes of administration was established.
Analytical verification of test item formulation:
The formulations investigated during the study were found to comprise
test item in the range of 91 to 102% and, thus, the required content
limit of +/- 10% with reference to the nominal content was met.
In addition, the test item was found to be stable in the formulations
when kept for 12 and 21 days in the refrigerator (4°C) due to results
which met the variation limit of 10% from the time-zero mean.
In conclusion, the results indicate that the accurate use of the test
item and distilled water as vehicle during this study. The formulations
were found to be homogeneously prepared (visual inspection) and
sufficient formulation stability under storage conditions was proven.
Repeated dose toxicity - oral:
90day repeated dose toxicity study :
A 90day repeated dose toxicity study is performed in rats. Male and
female animals were dosed via oral gavage at dose levels of 0, 10, 25 or
75 mg/kg/day, according to OECD guideline 408 (Edwards, 2016; K1, GLP).
The NOEL (NOAEL) for oral repeated dose toxicity is determined at 10
mg/kg/day (males) and 25 mg/kg/day (females). No toxicological relevant
effect was seen in mortality, clinical signs, water consumption,
ophthalmology, hematology, functional performance, sensory activity.
There was an overall reduction in body weight gain in males and females
at 75 mg/kg/d (accompanied by lower food conversion efficiency), and in
males dosed at 25 mg/kg/d. Males and females at 75 mg/kg/d showed a
significant increase in clinical chemistry parameters like aspartate
aminotransferase and alanine aminotransferase. Males treated at 75
mg/kg/d showed a statistically significant reduction in total protein.
Females treated at 75 mg/kg/d showed a significant increase in liver
weight. Toxicologically relevant findings in liver and kidney were
primary observations in the study were 1) vacuolation
in liver and spleen of males and females treated at 75 mg/kg bw/day and
single-cell necrosis (Grade: minimal) in the liver of males and females
at 75 mg/kg/day and males at 25 mg/kg/day. Regarding
in the liver and spleen,
the vacuoles observed are considered transient and non-adverse based on
scientific peer-reviewed literature regarding weakly basic aliphatic
amines and supporting evidence from similar compounds within the same
chemical family of aliphatic amines. Regarding
necrosis observed in the liver, the observation was described as “Centrilobular
single-cell necrosis at a minimal level”. This
description does not meet the criteria of “multi-focal
stated in the ECHA Guidance
on the Application of the CLP Criteria for
consideration of STOT RE classification. Therefore,
these effects do not, by themselves or together, indicate “significant”
toxicity in relation to Specific Target Organ Toxicity - Repeated
Exposure (STOT RE) classification in GHS. Since these observations in
the OECD 408 study are considered not to support STOT RE classification,
the substance is not classified.
Combined repeated dose toxicity with screening
A combined repeated dose toxicity study with the
reproduction/developmental toxicity screening test is performed in rats,
in which male and female rats are exposed to 0 (vehicle), 25, 100, 250
mg/kg bw/d via gavage (OECD 422).
The NOAEL for oral repeated dose toxicity in Sprague-Dawley rats
is considered to be < 25 mg/kg bw/day (actual dose received) for both
sexes. Male and female animals dosed at 100 and 250 mg/kg showed
significant effects of toxicity. One female group 4 dam dosed at 250
mg/kg was found dead on lactation day 1 and all its neonates were found
dead. All other female animals survived until their scheduled sacrifice.
Besides adverse clinical signs and effect on body weight and food
consumption, groups 3 and 4 animals exhibited adverse microscopic and
macroscopic liver findings, effects on liver weights, urea levels, and
liver enzymes including AST and ALT. Microscopic liver findings included
enlargement and pallor secondary to hepatocyte vacuolation and
centrilobular fibrosis, which severity increased proportionally with
dose levels. In addition at 100 and 250 mg test substance/kg induced
cytoplasmic vacuolation also occurred in the chief cells of the
parathyroid gland (high dose groups only), tracheal, bronchial and
bronchiolar epithelium, and within the media of the pulmonary
vasculature. Additional findings included foam cells in the splenic red
pulp (high dose groups only), decreased cellularity of the splenic
marginal zone (high dose group only), and erosion on the glandular
gastric mucosa. At 25 mg/kg microscopic findings were limited to the
gastric mucosa of one animal and the liver of another animal.
After the last day of dosing on day 40 the satellite animals stayed on
study for an additional 16 days without dosing to observe the
reversibility, persistence or delayed occurrence of systemic toxic
All male and female animals survived until their scheduled sacrifice on
day 57 (17 days after their respective last day of dosing). Clinical
observations in group 6 animals included instance of food crumbling,
piloerection, staining on the head (cranial) and red discharge around
the muzzle and nares with associated stained forepaws. Body weights and
food consumption was variable between male and female satellite animals.
Similar group 3 and 4 animals, unmated group 6 satellite animals dosed
at 250 mg/kg exhibited adverse microscopic and macroscopic liver
findings, effects on liver weights and liver enzymes.
All microscopic findings described for mated groups 3 and 4 animals
above were also present after the 16 day recovery period in the unmated
group 6 animals. The severity was similar or reduced grade except for
hepatic fibrosis, which was more preeminent in livers from recovery
groups. In conclusion, the toxic effects seen at 250 mg/kg in mated
group 4 animals were not reversible after a 16 day recovery period
without dosing in the unmated group 6 satellite animals.
Repeated dose toxicity - dermal/inhalation:
A key study is available for the oral route of exposure. According to
the REACH Regulation, only one route of exposure should be tested for
repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore,
it is not necessary to perform a repeated dose toxicity study via the
dermal or inhalation route of exposure.
Based on the proposed mechanism of action of osmotic effects and
the observation of transient vacuolization in other aliphatic amines,
this observation of vacuolization is considered also to be transient and
non-adverse and as such the effects are of minimal toxicological
importance. Regarding necrosis observed in the liver, the observation
was described as “Centrilobular single-cell necrosis at a
minimal level”. This description does not meet the criteria of “multi-focal
or diffuse”as stated in the ECHA Guidance on the
Application of the CLP Criteria for consideration of STOT RE
classification. Therefore, these effects do not, by themselves or
together, indicate “significant” toxicity in relation to Specific Target
Organ Toxicity Repeated Exposure (STOT RE) classification in GHS. Since
these observations in the OECD 408 study are considered not to support
STOT RE classification, the substance is not classified.
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