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EC number: 500-051-3
CAS number: 26780-96-1
NOEL for repeated dose toxicity is considered to be 250 ppm (11.8 mg/kg-bw/day) in a chronic 2-years study in rats
The most comprehensiverepeated dose toxicity study with TMQ is a chronic
2 years study in rats. TMQ was administered to groups of 60 SD
rats/sex/dose at dietary levels of 0, 50, 250, or 1000 ppm (approx. 0,
2.3, 11.8 or 48 mg/kg-bw/day for males and approx. 0, 3.1, 15.3 or 63
mg/kg-bw/day for females, respectively). 10 Animals /sex/dose were
sacrificed at month12, the remaining survivors were sacrificed at
termination, month 24. Analytical verification of stability of the test
material, homogeneity and concentration of test material in the diet was
performed. In-life observations included detailed clinical observations,
body weight and food consumption and ophthalmic examination of all
animals pretest and at termination. Hematology, blood chemistry and
urine analysis was performed for 10/sex/dose at months 3, 6, 12, 18, 24.
Gross pathology was reported for all animals at sacrifice and the
following organs were weighted: adrenals, brain, heart, kidneys, liver,
spleen, testes (with epididymides). Histopathology was reported for the
following tissues for control and high dose groups: aorta, adrenals,
bone and bone marrow, brain, caecum colon, duodenum, esophagus, eyes,
Harderian gland, heart, ileum, jejunum, kidneys, any lesions observed in
gross pathology, liver, lung, lymph node, muscel, ovaries, nasal
turbinates, pancreas, pituitary, prostate, rectum, sciatic nerve,
seminal vesicles, skin (with mammary tissue), spinal cord (cervical,
thorax, lumber), spleen, stomach, submaxillary salivary gland, testes
with epididymes, thymus, thyroid/parathyroid, trachea, uterus (corpus
and cervix), urinary bladder. Potential target tissues were investigated
in the mid and low dose groups. In addition a cellular proliferation
assay was performed and will be reported in the carcinogenicity chapter.
Analytical verification of stability of the test material, homogeneity
and concentration of test material in the diet gave satisfactory
results. Compared with their respective controls, survival at the end of
the study was greater at the high level in both males (61 ves 40%) and
females (59 vs 48%). These results are not indicative of toxicity. Body
weight was significant lower for females from week 11 to week 77; no
effect in males. There were no consistent compound related effects on
food consumption, clinical observations, ophthalmic examinations,
hematology, blood chemistry, urine analysis. Absolute liver weights were
increased in high dose males and females; liver weight relative to brain
weight was increased in mid dose females. There were no other organ
weights attributed to administration of the test material. There were no
gross necropsy alterations attributed to administration of the test
material. Histopathologic observation in the high dose groups indicated
increased incidences of centrilobular hepathocellular vacuolization and
Slightly increased incidences of bile duct
proliferation/cholangiofibrosis, adrenal cortical cystic degeneration
and of sinusoidal ectasia/cyst formation in high level males were
regarded as spontaneous lesions commonly observed in aged male rats. It
is possible that the increased incidences reflect more animals being at
risk for a longer period of time, i.e. as a result of the higher
survival rate in this group. The hyperplasia in the adrenal medulla is
also regarded as a spontaneous lesion this lesion is frequently observed
in aged males and no consistent dose response is observed.
An increased incidence of thyroid follicular adenomas/cystadenomas in
the high level males and females was considered to have resulted from
compound administration, but may have resulted from compensatory
mechanisms as a result of the hepatic toxicity and will be discussed in
the carcinogenicity chapter.
In conclusion: the observations in the mid dose group were not regarded
as toxicological significant because the lesion observed during
histopathology are commonly observed in aged rats and the liver weight
was only increased relative to brain weight. Overall the
No-Adverse-Effect-Level for repeated dose toxicity is considered to be
250 ppm in males and females (11.8 mg/kg-bw/day). Target organs are
liver and adrenal glands.
Based on the available information no classification is required
according to the EU classification criteria 67/548/EWG and regulation
no. 1272/2008 (GHS).
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