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 on methyltetrahydrophthalic anhydride (THPA), this based on changes in clinical chemistry parameters, changes in organ weights and inflammation of the forestomach mucosa.
Dermal and inhalation:
In accordance with REACH Regulation 1907/2006 (Annex IX, Column 2), assessment of repeated dose toxicity by dermal or inhalation exposure is not required as data are available for the (default) 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

Various studies have been undertaken on tetrahydromethylphthalic anhydride (MTHPA). This is a structural analogue of 3 -MTHPA D4 in which the methyl substitution is not defined or fixed in a specific position on the carbon cyclic structure, as opposed to 3 -MTHPA D4 where the methyl substitution is fixed at the 3C position. 3 -MTHPA D4 is regarded as a specific isomer of MTHPA.

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 concerns regarding animal welfare and the use of animals for experimental purposes. 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 REACH Regulation 1907/2006 (Annex IX Column 2) assessment of repeated dose toxicity by dermal or inhalation exposure is not required as data are available for the (default) oral route. The most relevant exposure route of this substance to investigate systemic toxic effects is regarded as oral. Inhalation or dermal exposure gives rise to local effects (sensitising and irritating effects) which 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 available, classification of the tetrahydromethylphthalic anhydride isomer 3 -MTHPA D4 is not justified according to the criteria given in Directive 67/548/EEC (CLP) or Regulation 1272/2008 (GHS).