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EC number: 202-723-9
CAS number: 99-04-7
In a combined repeated dose/ reproductive and developmental
toxicity test according to OECD guideline 422, rats were exposed to 30,
100, 300 and 1000 mg/kg bw/day m-toluic acid for 41 to 45 days,
resulting in an NOAEL of 1000 mg/kg bw/day for male animals due to an
absence of adverse effects and an NOAEL for females of 100 mg/kg bw/day
based on increased relative and absolute liver weight and the periportal
hepatocyte vacuolar swelling.
In the combined repeated dose/ reproductive and developmental
toxicity test according to OECD guideline 422, 10 male and 10 female SD
rats were exposed orally via gavage to 0, 30, 100, 300 and 1000 mg/kg
bw/day m-toluic acid for 41 to 45 days.
No deaths were observed in male and female animals in each group.
In males of the 1000 mg/kg bw/day dose group, the following
effects were observed: slightly decreased locomotor activity, increased
prothrombin time and increased aspartate aminotransferase values. The
statistical significantly increased prothrombin time (14.3 sec) is,
although being statistical significant, still within the historical
control range for that rat strain (13.3 - 16.5 sec, Lee et al. 2012),
thus should be regarded as incidental finding with no biological
relevance. The slightly decreased locomotor activity is regarded as
transient finding, in the absence of further interrelated clinical or
pathological findings should be regarded as not biological relevant. The
increased aspartate aminotransferase (AST, 77 ±13 IU/L) might indicate a
correlation with the histopathological findings in the liver in the
female animals, however the value is still well within the historical
control range of that rat strain (48.9-122.7 IU/L). Thus, an NOAEL of
1000 mg/kg bw/day was identified for male animals.
In females of the 1000 mg/kg bw/day dose group, the following
effects were observed: significant increase of absolute and relative
liver weights and periportal hepatocellular vacuolar degeneration. In
females of the 300 mg/kg bw/day dose group, periportal hepatocellular
vacuolar degeneration was observed with a grading of minimal to moderate
severity. Vacuolar degeneration, also termed cell swelling,
characterises a reversible cell injury, occurs in most types of acute
injury (Ed.: Haschek, WM et al. 2007 Fundamentals in toxicologic
pathology, AP; p. 13). In combination with increased liver weight, this
is a common finding in animals being exposed to high doses of
xenobiotics and commonly reverses if the injurious stimulus is removed
(Ed.: Haschek, WM et al. 2007 Fundamentals in toxicologic pathology, AP;
p. 201f). In the absence of degenerative cell lesions, such as necrosis
or apoptosis, and based on the minimal to mild manifestation of that
injury, this finding is considered a very mild adverse effect. Based on
the increased relative and absolute liver weight and the periportal
hepatocyte vacuolar swelling, the NOAEL for females was considered at
100 mg/kg bw/day.
In a repeated dose toxicity study with reproductive toxicity
screening, female rats showed effects, primarily manifested in increased
relative and absolute liver weight and the periportal hepatocyte
swelling. Such mild and reversible findings do not meet the criteria for
the classification as specific target organ toxicant (STOT-RE) in
accordance with Regulation (EC) No. 1272/2008 section 3.9. No evidence
of organ dysfunction or significant adverse changes in biochemistry
parameters were observed (cf. section 184.108.40.206.1 in Annex I of regulation
Thus, in accordance to the criteria of REGULATION (EC) No 1272/2008 and
its subsequent adaptations, m-toluic acid does not have to be classified
and has no obligatory labelling requirement for Specific target organ
toxicity by repeated exposure (STOT-RE).
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