1,2,3,6-tetrahydro-4-methylphthalic anhydride

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

1995-11-28 to 1997-06-05

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1997

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrahydromethylphthalic anhydride

EC Number:

234-290-7

EC Name:

Tetrahydromethylphthalic anhydride

Cas Number:

11070-44-3

IUPAC Name:

3a-methyl-3a,4,5,6-tetrahydro-2-benzofuran-1,3-dione

Details on test material:

- Name of test material (as cited in study report): tetrahydromethyl-1,3-isobenzofuranedione
- Analytical purity: 99.7%
- Lot/batch No.: 2522
- Stability under test conditions: stable
- Storage condition of test material: room temperature, dark place
- Molecular formula (if other than submission substance): C9 H10 O3
- Molecular weight (if other than submission substance): 166.18
- Smiles notation (if other than submission substance): O=C(OC(=O)C1CC=C(C2)C)C12
- InChl (if other than submission substance): 1/C9H10O3/c1-5-2-3-6-7(4-5)9(11)12-8(6)10/h2,6-7H,3-4H2,1H3
- Structural formula attached as image file (if other than submission substance): see Fig. (11070-44-3 structure.png)

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles river Japan
- Age at study initiation: purchase at 5 weeks old. Study is initiate at 6 weeks old
- Weight at study initiation: male 172.1-193.1g, female 125.4-139.9g
- Fasting period before study: from 17:00 on before day to after 3hr on dosing
- Housing:2-3 animals in polycarbonate cage with wood tip
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period:1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26°C
- Humidity (%): 45-65%
- Air changes (per hr): 13 times/hr
- Photoperiod (hrs dark / hrs light): 12/12 AM07:00-PM07:00

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: corn oil (10ml/kg)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 5, 10 and 20 w/v% in vehicle
- Amount of vehicle (if gavage):10mL/kg
- Justification for choice of vehicle: Corn oil is generally used
- Lot/batch no. (if required): V5P5523 Nakalai Tesque

MAXIMUM DOSE VOLUME APPLIED: 10mL/kg

CLASS METHOD
- Rationale for the selection of the starting dose: From results of prestudy (500, 1000 and 2000mg/kg p.o.). All animals did not die. at 2000mg/kg the body weight is decreased.

Doses:

0(Vehicle), 500, 1000 and 2000 mg/kg/day (in corn oil)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observation: more than one time/day. weighing: day 0, 2, 4, 6, 8, 11 and 15.
- Necropsy of survivors performed: (yes)/no
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: histopathology: In representative case,
histopathology observation was performed on stomach.

Statistics:

average and standard deviation (weight, per group)

Results and discussion

Preliminary study:

From results of prestudy (500, 1000 and 2000mg/kg p.o.). All animals did not die. at 2000mg/kg the body weight is decreased.

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No deaths prior to schedule termination.

Clinical signs:

other: Hypoactivity, bradypnea and prone position were observed in males and females of the 2000 mg/kg group on the day of administration.

Gross pathology:

At necropsy, thickening of the forestomach mucosa was observed in males and females of the 1000 and 2000 mg/kg group.
Adhesion of forestomach and liver was noted in one female of the 2000 mg/kg group.

Other findings:

Histopathology:
Squamous hyperplasia and granulomatous inflammation in submucosa of the forestomach were observed, and a squamous hyperplasia was also noted.
Squamous hyperplasia of the forestomach
1000mg/kg : male (2/5), female (1/5)
2000mg/kg : male (5/5), female (5/5)
(Squamous hyperplasia and granulomatous inflammation was observed in representative case of in males and females of the 1000 and 2000mg/kg group)
Adhesion of forestomach and liver and a foreign body granuloma in the adhesion area
2000mg/kg : female (1/5)

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Oral LD50 values were >2000 mg/kg for rat. The major toxicity was squamous hyperplasia of the forestomach.

Executive summary:

In this study, tetrahydromethylphthalic anhydride (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 mucosa was observed in males and females of the 1000 and 2000 mg/kg groups most likely caused by the irritative properties of the test substance. Adhesion of forestomach and liver was noted in one female of the 2000 mg/kg group. Histopathologically, squamous hyperplasia and granulomatous inflammation in submucosa 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.