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Description of key information

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

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
12 mg/kg bw/day
Study duration:
chronic
Species:
rat

Additional information

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 hypertrophy.

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.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; glandular: adrenal gland

Justification for classification or non-classification

Based on the available information no classification is required according to the EU classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).