Registration Dossier

Administrative data

Description of key information

Oral:
A NOAEL of 100 mg/kg bw/day was determined in a combined repeated dose/reproduction toxicity study (OECD 422) in rats based on changes in clinical chemistry parameters, changes in organ weights and inflammation of the forestomach mucosa.
Dermal and inhalation:
In accordance with column 2 of REACH Annex IX, the test repeated dose toxicity after dermal exposure (required in section 8.6) does not need to be conducted because there is another repeated toxicity robust study available for the oral route.

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:
subacute
Species:
rat

Additional information

Oral:

In the key study (Izumi, 1997), tetrahydromethylphthalic anhydride (MTHPA) was administered by gavage at doses of 0, 30, 100 and 300 mg/kg/day for 49 days in males and from 14 days before mating to day 3 of lactation in females (total number of 38 days). All animals survived at all treated group, except three animals died by accident (one female in 30 mg/kg, one male in 300 mg/kg and one female in 300 mg/kg group). Salivation was transiently observed in males of 300 mg/kg group at the day 36-49. Histopathological examination revealed squamous hyperplasia of the forestomach in both sexes of the 300 mg/kg group, epithelial vascular change, edema and cellular inflammation of the forestomach in males of the 300 mg/kg group, and erosion of the forestomach in females of 300 mg/kg group. There were no adverse effects on body weight and food consumption. There were no alterations related to tetrahydromethyl-1, 3-isobenzofuranedione on hematological examination. Decreased total cholesterol and BUN and increased triglyceride were observed in males of the 300 mg/kg. As a gross finding, mucosal thickening of the forestomach was found in both sexes of the 300 mg/kg group. Increased adrenal weights were observed in males of the 300 mg/kg group.

The major toxicity was inflammation of stomach mucosa. On the basis of this study, NOEL is 30mg/kg/day (male), 100mg/kg/day (female) and NOAEL is considered to be100 mg/kg/day for both sexes.

No 90 day toxicity study with tetrahydromethylphthalic anhydride (MTHPA) is available. Taken all data from MTHPA and structural analogue substances together, a new 90 day toxicity study with MTHPA is not required and not in line with animal welfare ideas. The data available for chemically almost identical substances in different species and for exposure periods of 90 days support the findings noted in OECD 422 study taking the time extrapolation factor into account. Therefore, the OECD 422 study is considered to represent a reliable basis for DNEL derivation for MTHPA.

Dermal and inhalation:

In accordance with column 2 of REACH Annex IX, the test repeated dose toxicity after dermal exposure (required in section 8.6) does not need to be conducted because there is another repeated toxicity robust study available for the oral route (see IUCLID5 section 7.5.1).

The most relevant exposure route of this substance to investigate systemic toxic effects is oral. In case of inhalation or dermal exposure, sensitising and irritating effects occur before systemic toxicity becomes relevant.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Justification for classification or non-classification

On the basis of the data submitted, classification of tetrahydromethylphthalic anhydride (MTHPA) as harmful and labelling with Xn, R 48/22 (Harmful: danger of serious damage to health by prolonged exposure if swallowed) according to the criteria given in Directive 67/548/EEC and with STOT rep. exp. cat 2 according to CLP (GHS) is not justified.