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Description of key information

Repeated dose toxicity studies performed with the component TMP report NOAEL values of 100 and 200 mg/kg bw/d.  The NOAEL value in a 28 day TMP study was 0.3% in the diet. A testing proposal is included for CTF.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Repeated dose oral toxicity:

Studies are available for the component TMP and therefore (by read-across) for the component DMP. A 90-day oral repeat toxicity study with CTF in the rat (OECD 408) is proposed in order to address the toxicity of this component and fully characterise the toxicity of the substance.

Waivers are proposed for repeated dermal and inhalation toxicity, in accordance with Column 2 of Annex VIII/IX of the REACH Regulation. The repeated dose toxicity of the substance has been adequately elucidated by the oral route, with additional testing proposed for CTF. Further testing by the addtional routes of exposure is not required.

TMP studies

The oral toxicity of trimethylolpropane (TMP 99) was determined in a 90 day feeding study with male and female rats (de Knecht-van Eekelen and van der Meulen, 1969). The test substance was fed at 0, 0.03, 0.1, 0.3 and 1.0% in stock diet to groups of 10 male and 10 female rats. Rats were sacrificed and subject to necropsy at the end of the feeding period. General appearance and behaviour, body weight gain, food intake and efficiency, blood serum enzyme activities, serum protein content and urine composition were not affected by treatment. Haemoglobin content was decreased in 1.0% females, whilst packed cell volume and red blood cell counts were decreased in females at 0.3 and 1.0%. Blood smears contained normoblasts and white blood cell fragments in both sexes at 1.0% and normoblasts in females at 0.3%. The relative weight of the spleen was increased in both sexes. Liver, kidney and ovary weights were increased in 1.0% females. Pituitary weight was increased in males at 1.0%. Gross examination at autopsy revealed enlarged dark spleens in both sexes at 1.0%. Histopathology revealed increased numbers of cells in the red pulp of the spleen, and in the liver Kupffer cells laden with pigment, sinusoids containing normoblasts and too many small lymphocytes were revealed in the 1.0% group. It was therefore concluded that the 90 day NOAEL of TMP 99 is 0.1% in the diet, for male and female rats. This dose level is calculated to be equivalent to 100 mg/kg bw/d, using default conversion factors.

A combined repeat dose and reproductive/developmental toxicity screening test was conducted in male and female Slc:SD rats (MHLW, 1994), according to GLP. Trimethylolpropane was administered daily to the rats by gavage, at doses of 0 (vehicle control; distilled water), 12.5, 50, 200, 800 mg/kg bw/day. The rats were dosed for 2 weeks prior to mating, during the mating period and pregnancy until day 4 of lactation (approximately 45 days). There were no deaths or abnormal clinical signs attributable to treatment. The body weights of males and females in the 800 mg/kg group were lower than those of the control group during the premating period. Food consumption was not affected by treatment. Haematology and clinical chemistry investigations did not reveal any treatment-related abnormalities. Absolute and relative liver weights were significantly elevated in the 800 mg/kg males, and increased but not significantly in the 800 mg/kg females. Necropsy revealed hypertrophy of the liver in 3 male 800 mg/kg rats. Histopathological examination revealed no definite morphological lesions. Slight basophilic alteration of the renal tubular epithelial cells was observed in 1 female receiving 50 mg/kg, in 2 females receiving 200 mg/kg, and in 5 females receiving 800 mg/kg. These changes were not unequivocally attributable to the test substance administration, because of their limited distribution and limited degree, and because similar lesions were observed in male rats of all groups including the controls. The NOAEL was therefore considered to be 200 mg/kg bw/d in both sexes.

The oral toxicity of trimethylolpropane (TMP) was studied in a range finding test (Wijnands & Feron, 1969). The substance was fed at 0, 0.3, 1.0, 2.0 and 4.0% in the diet to albino rats, for a period of 28 days.

The LOEL = ca. 965 mg/kg bw/day (1%). Reduced body weights and decreased food efficiency were observed at the 4% level in both sexes. Haematology analyses conducted on day 25 revealed reduced haemoglobin values at the 2% and 4% levels. Red blood cell counts were decreased dose-dependently in the 1%, 2% and 4% groups. White blood cell counts were increased in the 4% group. Enlargement of the spleen and liver was observed at necropsy in the 2% and 4% animals. Relative liver, kidney, heart and spleen weights were significantly and dose-dependently increased in the 1%, 2% and 4% groups. Histopathological examination revealed treatment-related abnormalities in the spleen and liver of rats in the 1%, 2% and 4% group. Slight abnormalities in the kidney were noted in the 2% and 4% males.

The 28 day NOAEL is considered to be 0.3% (ca. 275 mg/kg bw/day).

Justification for classification or non-classification

There is no evidence of marked toxicity or any effects at relevant dose levels (<100 mg/kg bw/d), therefore no classification is proposed for repeated dose toxicity according to Directive 67/548/EEC or Regulation (EC) No 1272/2008.