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Administrative data

Description of key information

Oral:
Oral LD50 values were >2000 mg/kg for rat. The major toxicity was squamous hyperplasia of the forestomach.
Dermal:
The acute dermal median lethal dose (LD50) of the test material, tetrahydromethylphthalic anhydride, in the Sprague-Dawley strain rat was found to be greater than 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via dermal route

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Oral:

Different studies were available investigating acute oral toxicity of tetrahydromethylphthalic anhydride (MTHPA). The study by Furukawa (1997) was chosen as key study, as this is the only study which was conducted according to a Guideline (OECD 401) and GLP. LD50 values of the supporting studies are in the same concentration range as the key study (some slightly below) but are regarded as less reliable than the key study.

In the key study (Furukawa, 1997), MTHPA was studied for oral toxicity in rats in a single dose toxicity test at doses of 0, 500, 1000 and 2000 mg/kg for both sexes. No deaths occurred of either males or females. Clinical signs of hypoactivity, bradypnea and prone position were observed in males and females of the 2000 mg/kg group on the day of administration. Decrease of body weights was observed in males of the 2000mg/kg group and suppression of body weight gain was observed in females of the 2000mg/kg group on the day of administration. At necropsy, thickening of the forestomach mucosal was observed in males and females of the 1000 and 2000 mg/kg groups. Adhesion of forestomach and liver was noted in one female of the 2000 mg/kg group. Histopathologically, squamous hyperplasia and granulomatous inflammation in submucosal of the forestomach were observed in the 1000 and 2000 mg/kg groups. A foreign body granuloma in the adhesion area was also noted in the female of the 2000 mg/kg group. As the result, LD50 value was decided as >2000 mg/kg.

In a supporting acute oral toxicity study (Irie, 1969a), groups of T23-48:Donryu rats (6/sex) were given a single oral dose of MTHPA in olive oil at doses of 1160, 1390, 1660, 2000 and 2400 mg/kg bw and observed for 7 days.

Oral LD50 = 2102 mg/kg bw

In a supporting acute oral toxicity study (Irie, 1969b), groups of dd mice (10/sex) were given a single oral dose of MTHPA in olive oil at doses of 920, 1100, 1330, 1590, 1900, 2280, 2720 mg/kg bw and observed for 7 days.

Oral LD50 = 1707 mg/kg bw

In a supporting acute oral toxicity study (Sheena, 1980), groups of Crj: CD(SD) rats (105/sex) were given a single oral dose of MTHPA in olive oil at doses of 1000, 1600, 2000, 3200, 5000 and 6400 mg/kg bw and observed for 14 days.

Oral LD50 = 1900 mg/kg bw (1600-2900 mg/kg bw)

In a supporting acute oral toxicity study, groups of rats were given a single oral dose of MTHPA.

Oral LD50 = 2589 mg/kg bw

Dermal:

In the key study (Allen (1993), the acute dermal toxicity of the test material in the Sprague-Dawley strain rat was assessed. The method used followed that described in the OECD Guidelines for Testing of Chemicals (1981) No. 402 "Acute Dermal Toxicity" referenced as Method B.3 in Commission Directive 84/449/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

A group of ten animals (five males and five females) was given a single 24-hour, semi-occluded dermal application to intact skin at a dose level of 2000 mg/kg bw. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination.

There were no deaths. No signs of systemic toxicity were noted during the study. Very slight to well-defined erythema was noted at the

treatment sites of all animals. Other skin reactions noted were haemorrhage of the dermal capillaries and crust formation. Treatment sites appeared normal two to five days after dosing. All animals showed expected gain in bodyweight during the study. No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was found to be greater than 2000 mg/kg bodyweight.

In a supporting acute dermal toxicity study (Irie, 1969), Belgian Hare rabbits (1/dose) were dermally exposed to MTHPA either to a single dose of 242 and 1210 mg/kg bw (0.4 and 2 mL application volume) or daily for 3 days to a dose of 242 mg/kg bw/day (0.4 mL application volume). Animals then were observed for 14 days.

No mortality was observed. Incrustation was observed after 3 days when applied continuously.

Dermal LD50 > 1210 mg/kg bw (single dose)

Dermal LD50 > 242 mg/kg bw (continuous dosing over 3 days)

In a second, poorly documented supporting study by Smyth (1969), the LD50 in rabbits after dermal administration of MTHPA was determined to be 1706 mg/kg bw (single dose).

Justification for classification or non-classification

Based on the results obtained in the acute toxicity studies (oral: LD50 (rat) > 2000 mg/kg bw; dermal LD50 (rat) > 2000 mg/kg bw) and taking into account the provisions laid down in Council Directive 67/548/EEC and CLP (1272/2008/EC), MTHPA has not to be classified regarding acute toxicity.