Registration Dossier

Administrative data

Description of key information

Oral toxicity: Four studies are available, resulting in the following LD50's for the pure substance, weight-of-evidence (studies with 25% solution):
MB2005_1: 12.5 < LD50 < 125 mg/kg bw
MB2005_2: LD50 = 43.5 mg/kg bw
JSR2004: 12.5 < LD50 < 75 mg/kg bw
Supporting study (studies with 2.5% solution):
JSR2005: 7.5 < LD50 < 50 mg/kg bw
Dermal toxicity: Four studies are available, resulting in the following LD50's for the pure substance, weight-of-evidence (studies with 25% solution):
MLI 2005: 12.5 < LD50 < 50 mg/kg bw
Aventis 2001: LD50 = 112 mg/kg bw
JSR 2004: 50 < LD50 < 500 mg/kg bw
Supporting study (studies with 2.5% solution):
JSR 2005: 25 < LD50 < 50 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
12.5 mg/kg bw
Quality of whole database:
All four available studies were performed according to the relevant OECD guideline and GLP principles and have Klimisch score 1.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
12.5 mg/kg bw
Quality of whole database:
All four available studies were performed according to the relevant OECD guideline and GLP principles and have Klimisch score 1.

Additional information

Several weight of evidence studies concerning the acute oral toxicity are available:

An acute oral toxicity test was conducted equivalent to OECD 401 under GLP principles.Groups of 5 male or 5 female rats were dosed with either 50 or 500 mg/kg bw TMAH in a 25% aqueous solution.Only one female survived the highest dosage, all others died within 4 hours. No animals died at 50 mg/kg bw. Gross pathology revealed hemorrhages in the stomach of all dead animals, and two animals had livers protruded through diaphragms.No clinical signs or deviations in weight change were noted in the surviving animals. Based on these data, the LD50 for male and female rats after oral application was determined to be >50 mg/kg bw and < 500 mg/kg bw for the 25% aqueous solution. This corresponds to an LD50 >12.5 <125 mg/kg bw for the pure substance.

In another acute oral toxicity, conducted according to OECD 425 guideline under GLP principles, female rats were treated successively by gavage withaqueous solutions of the test substance, corresponding with 55, 175 and 550 mg/kg bw 25% TMAH. The female dosed with the highest concentration died, as well as 3/4 rats dosed with 175 mg/kg bw. All rats died within 4 hours and showed red areas on mucosal lining of the stomach. The surviving animals did not show anyclinical signs or deviations in weight change. Based on these data, the LD50 of 25% TMAH after oral application was determined to be 174 mg/kg bw, which corresponds to an LD50 of 43.5 mg/kg bw for the pure substance.

In a third acute oral toxicity study performed with TMA 25 (25% solution of TMAH) according to OECD 423 all animals at 300 mg/kg bw died and at 50 mg/kg bw no mortality was observed. The clinical signs observed, i.e. lethargy, tremors, flat posture, hunched posture, uncoordinated movements, ptosis, squeaking and piloerection had disappeared by day 2. The LD50 was determined to be within the range 50 -300 mg/kg bw, corresponding to 12.5 - 75 mg/ kg bw for the pure test substance.

In a supporting acute oral toxicity test performed according to OECD 423, no mortality occurred at 300 mg/kg bw, but all three animals died/were killed at 2000 mg/kg bw. Hunched posture was noted at 300 mg/kg bw on day 1. At 2000 mg/kg bw hunched posture, lethargy, flat posture, slow breathing, laboured respiration and/or ptosis were seen. Reduced body weight gain and body weight loss was noted at 2000 mg/kg bw. Macroscopic examination of animals that died revealed reddish discolouration of the glandular mucosa of the stomach in one female. The LD50 was determined to be within the range of 300 -2000 mg/kg bw, which corresponds to an LD50 of 7.5-50 mg/kg bw for the pure substance.

Several weight of evidence studies concerning the acute dermal toxicity are available:

An acute dermal toxicity test was performed with male and female rats according to OECD guideline 402 and GLP principles. At 1000 and 2000 mg/kg bw, only female rats were tested, which all became comatose and died during exposure. At 200 mg/kg bw, 3 of the 5 males and all females died the first day after start of the exposure. Necropsy of dead animals revealed abnormal changes in skin and mottled livers. No mortalities were found at 50 mg/kg bw. The surviving animals did not show any abnormal changes in body weight. Surviving animals showed mottled kidneys, and slight effects on the skin, consisting of slight oedema and eschar formation which did not fully reverse within 14 days. The dermal LD50 of an aqueous solution of 25% TMAH was found to be greater than 50 mg/kg bw but less than 200 mg/kg bw. This corresponds to an LD 50 between 12.5 and 50 mg/kg bw for the pure substance.

In addition, an acute dermal toxicity test with 25% tetramethylammonium hydroxide was performed according to OECD guideline 402 and GLP principles. Female rats were exposed to 200, 400 or 500 mg/kg bw, male rats were exposed to 400 mg/kg bw. None of the male rats died, whereas 2/5 females died at 400 mg/kg bw and 3/5 at 500 mg/kg bw. Death occurred on first day after exposure, clinical signs included irregular respiration, decreased respiration rate and convulsion (prior to death). No effects on the skin of exposed animals were observed. The LD50 for female rats was found to be 449.1 mg/kg bw, this is equivalent to an LD50 of 112.275 mg/kg bw for the pure substance.

In another acute dermal toxicity study with TMA 25 performed according to OECD 402, the three animals exposed at 1000 and 2000 mg/kg bw all died within one day. Clinical signs included restlessness, tremors, hunched posture and/or squeaking at 1000 and 2000 mg/kg bw. At 200 mg/kg bw flat posture, hunched posture, quick breathing, shallow respiration and chromodacryorrhoea were seen. No abnormalities were observed at macroscopy. The dermal LD50 of TMA25 in Wistar rats was established to be in the range of 200-1000 mg/kg bw, which corresponds to an LD50 of 50-250 mg/kg bw of the pure substance.

In a supporting acute dermal toxicity study with TMA248WA performed according to OECD 402, the three animals exposed to 2000 mg/kg bw died/were sacrificed. At 200 and 1000 mg/kg bw no mortality occurred. Clinical signs observed at 2000 mg/kg bw included restless behaviour, clonic spasms, hunched posture, uncoordinated movements and laboured respiration. At 1000 and 200 mg/kg bw flat posture and/or chromodacryorrhoea were seen. No abnormalities were observed at macroscopic examination.

The dermal LD50 of TMA248WA in Wistar rats was established to be in the range of 1000-2000 mg/kg bw, which is equivalent to 25 - 50 mg/kg bw for the pure substance.

The studies for oral acute toxicity result in LD50's in the same range. Also for the dermal toxicity studies, the results are in comparable ranges. Furthermore, in several available studies, physical signs including coma, ataxia, lethargy, tremors, uncoordinated movements were reported at 44 mg/ kg bw and higher (oral exposure) and 50 mg/kg bw and higher (dermal exposure).


Justification for selection of acute toxicity – oral endpoint
The LD50 of TMAH was determined with a weight of evidence approach. Three studies with 25% TMAH are used. From these, the worst case scenario resulted in an LD50 of >12.5 to <75 mg/kg bw for pure TMAH. A fourth study was used as supporting data, since it is performed with TMAH at 2.5% concentration.

Justification for selection of acute toxicity – dermal endpoint
The LD50 of TMAH was determined in a Weight of Evidence approach. Three studies with 25% TMAH are used. From these, the worst case scenario resulted in an LD50 of 12.5 - 50 mg/kg bw for pure TMAH. A fourth study was used as supporting data, since it is performed with TMAH at 2.5% concentration.

Justification for classification or non-classification

Based on the oral LD50 of 12.5 - 50 mg/kg bw and dermal LD50 of 12.5 - 50 mg/kg bw as extrapolated from the studies performed with 25% TMAH, pure TMAH is classified in category 2 for oral and category 1 dermal toxicity according to CLP Regulation (EC) No. 1272/2008.

Based on the severe clinical effects observed indicating an effect on the central nervous system, TMAH is classified STOT Single Exp. 1 according to CLP Regulation (EC) No. 1272/2008.