Tetrahydromethylphthalic anhydride

Endpoint summary

Description of key information

Following a read-across on data available for 4-MHHPA obtained in a subchronic oral toxicity study in rats according to EU test methods and OECD guidelines, the NOAEL for MHHPA for males and females was determined to be 450 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Please refer to IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

450 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed.

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

450 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Well described GLP compliant study conducted to recognized international test guidelines.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A short-term oral toxicity study for reproductive screening according to OECD 422 is available for the test item MTHPA.

Long-term toxicity of MTHPA following repeated oral administration was assessed from read-across data available for the structural analogue 4-MHHPA as similar chemical and toxicological properties were assumed. The experimental design and the results of the source-studies from the structural analogue 4-MHHPA are considered to cover the key parameters adequately, with an exposure duration comparable to or longer than the corresponding study. Therefore this data is deemed to be relibale and also adequate for the purpose of classification and labelling and/or risk assessment.

 

Key study:

 

OECD 408:

The structural analogue 4-MHHPA was examined for its possible health hazards after repeated exposure in a sub-chronic GLP compliant study according to OECD 408. A four weeks recovery period in the high dose and control dose animals was included in order to assess reversibility, persistence or delayed occurrence of potential toxicological effects.

The test item was administered orally (by gavage) to male and female Han: WIST rats (n=15 animals/sex in the control and high dose groups, n= 10 animals/sex in the low and middle dose groups) once a day at 0 (vehicle control), 50,150 and 450 mg/kg bw/day doses (dose volume of 5 mL/kg bw) for 90 or 91 days. Five animals/ sex in the control and high dose groups assigned to the recovery groups were treated identically up to Day 89 then they were observed without administration for four weeks (recovery observations). Concentrations of the test item in the dosing formulations varied between ranges of 93 % and 108 % of nominal concentrations at each analytical occasion confirming proper dosing.

Animals were observed for mortality twice a day during the course of the study. Daily general clinical observations and weekly detailed clinical observations were performed. A functional observation battery was conducted in the last week of treatment. The body weight was determined twice weekly for four weeks (weeks 1-4) then once weekly during the course of the treatment and recovery periods. Food consumption was measured and evaluated weekly. The estrous cycle of each female animal was examined for two weeks before necropsy and for two weeks before the end of the recovery period. Clinical pathology examinations (including hematology, blood coagulation and clinical chemistry) and gross pathology were conducted one day after the last treatment and at the end of the recovery period. The absolute and relative weights of selected organs were measured. Sperm examinations were conducted in animals of the control and high dose groups at termination of the treatment. Full histopathology was performed on the preserved organs or tissues of the animals of the control and high dose groups including recovery groups. Additionally, liver and seminal vesicles in single male animals at 150 mg/kg bw/day were processed and evaluated histologically on the basis of necropsy observations.

No animals died during the course of the study and no signs of toxicity related to the test item were detected at any dose level at the daily and detailed weekly clinical observations or in the course of the functional observation battery. The behavior and physical condition of animals were normal during the entire observation period. Test item related nuzzling up the bedding material and salivation were observed in male animals at 50, 150 and 450 mg/kg bw/day with different incidence and duration during the treatment period. Animals salivated shortly after the daily administration of the test item and it ceased shortly thereafter and was therefore judged to be not adverse. The body weight development was unaffected by the test item at 50, 150 and 450 mg/kg bw/day (male and female animals) during the 3-month treatment period. The mean body weight was similar to the control in male and female animals at 450 mg/kg bw/day during the recovery period. Slight changes in the mean body weight gain were detected in male recovery animals. As the mean body weight remained similar to the control group, the changes were considered to be toxicologically not relevant. The mean daily food consumption was comparable in animals of the control and test item treated groups and no abnormalities in the eyes of animals in the high dose group at termination of the treatment were observed. No test item related influence on the estrous cycle was detected and hematological investigations did not reveal test item or treatment related changes in the examined parameters in male or female animals at any dose level. No pathologic test item effect was detected at the evaluation of clinical chemistry parameters and T4 and TSH levels were comparable in the control and test item treated groups at the end of the treatment and recovery periods. Test item induced macroscopic changes and changes in organ weights were not detected at termination of the treatment period or at the end of the recovery period. Sperm analysis did not reveal any test item related influence on the sperm parameters (count, motility and morphology) at 450 mg/kg bw/day. Histological examination did not reveal severe or permanent test item related lesions in the organs or tissues of animals administered with 450 mg/kg bw/day dose at termination of the treatment or at the end of the recovery period. Slight vacuolation of hepatocytes in the centrilobular region (hepatic lipidosis) in 3/10 female animals at 450 mg/kg bw/day was detected. As no such effect was observed in the recovery group, the observation was considered a mild, reversible and non-adverse test item related lesion.

Under the conditions of the present study, the test item did not cause adverse effects in male or female Han: WIST rats after consecutive 90/91-day oral (by gavage) administration at 50, 150 or 450 mg/kg bw/day. Vacuolation of hepatocytes in the centrilobular region (hepatic lipidosis) in some female animals at 450 mg/kg bw/day was assumed to be indicative of test item influence and was considered as a mild, reversible lesion in the female liver. Based on these observations the No Observed Adverse Effect Level (NOAEL) was determined to be 450 mg/kg bw/day for male and female Han:WIST rats.

 

 

Supporting study:

 

OECD 407:

The sub-acute oral toxicity of 4-MHHPA was investigated in rats according to EU test methods and OECD guidelines. No signs of toxicity were observed during the "in-life" phase of the study. Post mortem macroscopic observations, absolute and relative organ weights and microscopic examination did not show any changes indicating systemic toxicity of the substance. Thickening of the forestomach mucosa (non-glandular region) was noted in the majority of animals treated with 450 mg/kg bw/day and in 1 female treated with 150 mg/kg bw/day. Microscopic examination of these lesions revealed a slight to mild squamous hyperplasia of the forestomach mucosa (non-glandular region), often associated with submucosal oedema, inflammatory reaction or erosion of the gastric mucosa. These changes were no longer present after 2 weeks of recovery. According to the results of the read across the NOAEL for MHHPA was considered 450 mg/kg bw/day and the NOEL for MHHPA was considered 50 mg/kg bw/day.

 

 

OECD 422:

In the short-term study (Izumi, 1997) with the test item, 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 be 100 mg/kg/day for both sexes.

 

 

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 IUCLID 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.

 

 

Conclusion:

As an overall conclusion no adverse effects regarding repeated dose toxicity have been identified and the NOAEL was determined to be 450 mg/kg bw/day for the structural analogue hexahydro-4 methylphthalic anhydride (4-MHHPA). According to the results of the read across the NOAEL of 450 mg/kg bw/d is considered for the registration substance MHHPA for repeated dose toxicity.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available studies are considered reliable for this assessment.

 

Repeated dose toxicity, oral:

Based on the above stated assessment of the specific target organ toxicity potential after repeated oral exposure of the test substance, the compound does not need to be classified according to Regulation (EC) No 1272/2008 of the European Parliament and of the Council No 1272/2008 (CLP), as amended for the eighteenth time in Regulation (EU) 2022/692.