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EC number: 701-008-3
CAS number: -
Dose Formulation Analyses
The mean % nominal concentration should be
between 85% to 115% and with a relative standard deviation (RSD) 10.0%.
Results were within these criteria. The test article was not detected in
the control samples.
The objective of the study was to
determine the toxicity of the test article,
Benzyl 3‑isobutyryloxy-1-isopropyl-2,2-dimethylpropyl phthalate a
Reaction Mass of Benzyl (1R,1S)
benzene‑1,2-dicarboxylate and Benzyl (3R,3S)
benzene-1,2-dicarboxylate, following daily oral (gavage) administration
to the rat for 90 days. Four groups of 10 male and 10 female Crl:WI(Han)
strain rats were assigned to the main study phase. Animals were
administered 0 (vehicle), 100, 300, or 1000 mg/kg/day of the test
article for up to 90 consecutive days, by oral gavage at a dose volume
of 4 mL/kg. The vehicle was corn oil.
Assessment of toxicity was based on
mortality, clinical and postdose observations, body weights, food
consumption, ophthalmic examinations, and functional observational
battery and oestrus cycle (females only) assessments. At the end of the
main study phase, blood samples were collected for haematology,
coagulation, clinical chemistry, and thyroid hormone assessments.
Necropsies were performed on all animals following 90 days of dosing,
and any macroscopic abnormalities were recorded. Selected organs were
also weighed. Microscopic examinations were performed on selected
tissues from control and high dose animals. A test article-related
effect was noted in the liver and thyroid glands; therefore, these
tissues were also examined from low and intermediate dose animals to
establish a no observed adverse effect level (NOAEL).
No test article-related deaths
occurred. Salivation was evident for all test article-treated groups,
and on occasion, for control females. Paddling behaviour was observed
postdose for up to five animals administered 300 or 1000 mg/kg/day, and
a dose response was observed. In the absence of any microscopic findings
that suggested irritancy, these findings were considered attributable to
an unpalatable or unpleasant tasting test article formulation and
considered not to represent systemic toxicity of the test article. No
adverse effect on body weight change or food consumption was noted for
test article-treated animals, compared with controls. Weekly open-field
arena observations did not reveal any toxicologically significant
effects of the test article. Grip strength, foot splay, and locomotor
activity were unaffected by the test article at all dose levels. No
difference in the stage of oestrus was noted for test article-treated
females, compared with controls and no ocular changes were noted at any
dose level at the end of the dosing phase. No toxicologically important
haematology changes were noted for test article-treated animals,
compared with controls.
Creatinine levels for males
administered 1000 mg/kg/day were significantly lower than controls.
Blood urea nitrogen and urea levels were also significantly lower for
males administered 1000 mg/kg/day, compared with controls. No such
effects were noted for females administered 1000 mg/kg/day. Elevated
cholesterol levels were evident for males administered 300 or
1000 mg/kg/day and for females administered 1000 mg/kg/day, compared
with controls.These increases may be associated with the liver and
thyroid gland changes noted.
Total thyroxine was reduced and
thyroid stimulating hormone was increased for both sexes administered
1000 mg/kg/day, compared with controls; the effect was more pronounced
in males. Thyroid/parathyroid weights were higher for males administered
300 or 1000 mg/kg/day and females administered 100 or 1000 mg/kg/day,
compared with controls. Microscopic examination revealed follicular cell
hypertrophy for all males and most females administered 1000 mg/kg/day,
with the effect also evident following 300 mg/kg/day administration.
Enlarged livers and corresponding
elevated liver weights were noted for males administered 1000
mg/kg/day. Liver weights were also higher for females administered
1000 mg/kg/day, males and females administered 300 mg/kg/day, and males
administered 100 mg/kg/day, compared with controls. Microscopic
examination revealed centrilobular hepatocyte hypertrophy and all
animals administered 1000 mg/kg/day, all males and some females
administered 300 mg/kg/day, and most males and some females administered
In conclusion, once daily oral gavage
administration of Benzyl 3-isobutyryloxy-1-isopropyl-2,2-dimethylpropyl
phthalate a Reaction Mass of Benzyl (1R,1S)
benzene-1,2-dicarboxylate and Benzyl (3R,3S)
benzene-1,2-dicarboxylate at 100, 300, or 1000 mg/kg/day, for
up to 90 consecutive days resulted in test article‑related
changes at all dose levels, which generally consisted of changes in the
liver and thyroid gland, however, these were considered to be adaptive
changes and not adverse. Therefore, the no observed adverse effect level
(NOAEL) was considered to be 1000 mg/kg/day.
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