Dimethyl isophthalate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: 13-week repeated dose toxicity study conducted by the US National Cancer Institute. Precedes establishment of GLP.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

no

Remarks:

precedes establishment of GLP

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl terephthalate

EC Number:

204-411-8

EC Name:

Dimethyl terephthalate

Cas Number:

120-61-6

Molecular formula:

C10H10O4

IUPAC Name:

dimethyl terephthalate

Test material form:

solid: crystalline

Details on test material:

obtained from Eastman Chemical Products Inc., Kingsport, TN, USA. Lot C4B (crystalline powder) or Lot EC No. 2/27/76 as briquette ground to a fine powder before use, 99.99-100% pure. (Impurity not identified).

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Frederick Cancer Research Center, Frederick, MD, USA.
- Age at study initiation: 7 weeks
- Weight at study initiation: 87.6 +/- 3.2 g (males), 70.0 +/- 2.9 g (females)
- Housing: Polycarbonate, with Betta-chip bedding (Northeastern Products Corpl, Warrensburg, NY, USA
- Diet (e.g. ad libitum): ad libitum, Wayne Lab Biox, Allied Mills, Inc. Chicago, IL
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 45-55%
- Air changes (per hr): 12 times per hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: feed

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): basal diet, Wayne Lab-Blox meal (Allied Mills, Inc. Chicago, IL, USA) using Patterson-Kelly twin-shell blender fitted with an intensifier bar.
- Storage temperature of food: room temperature

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil, as dust suppressant
- Concentration in vehicle: 2% of initial weight
- Lot/batch no. (if required): source: Duke's Corn Oil, C.F. Sauer Co., Richmond, VA, USA

Control animals received the basal diet containing 2% corn oil.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration of test material was determined for randomly selected batches of formulated diet. The mean analytical concentration for the checked samples was within 4.3% of the theoretical concentration, with a coefficient of variation of 5.7%.
Duplicate 4 g samples of diets were agitated with 10 ml of benzene and supernatant was analyzed by gas chromatography using a flame ionization detector. Spiked samples and a feed blank were included. All tests were conducted at Hasleton Laboratories.

Duration of treatment / exposure:

13 week dose-range finding study for 103 week lifetime bioassay

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
1750 to 20000 ppm
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Details on study design:

Dose selection rationale: based on 14-day toxicity study results.
Doses in the 13-week study were (ppm): 1750, 2500, 5000, 10000, 20000.

Examinations

Observations and examinations performed and frequency:

Animals were observed twice daily. Clinical signs and the presence of palpable masses were recorded every week. Mean body weights and food consumption were recorded every week.

Sacrifice and pathology:

Animals were sacrificed by exsanguination under sodium pentobarbital anesthesia (Diabutal, Diamond Laboratories Inc., Des Moines, Iowa) and necropsied. The pathologic evaluation consisted of gross and microscopic examination of major tissues, major organs, and all gross lesions. The tissues were presevered in 10% buffered formalin, embedded in paraffin, sectioned and stained with hematoxylin and eosin. The following tissues were examined microscopically: brain, pituitary, spinal cord, eyes, esophagus, trachea, salivary gland, mandibular lymph node, thyroid, parathyroid, heart, thymus, lungs and mainstem bronchi, liver, pancreas, spleen, kidney, adrenal, stomach, small intestine, colon, urinary bladder, prostate or uterus, testes or ovaries, sternebrae, femur and mammary gland, and any tissue masses.

Necropsies were also performed on all animals found dead.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

no deaths

Mortality:

no mortality observed

Description (incidence):

no deaths

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

decreased in males and females at the two highest doses

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

diffuse hepatocellular swelling, not dose-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

All rats survived until the end of the study. Decreases in body weight gain occurred in males and females fed 10000 and 20000 ppm. No gross lesions were observed in rats at necropsy. Microscopic examinations of livers of treated rats showed diffuse hepatocellular swelling which was not dose-related.

Effect levels

Dose descriptor:

NOAEL

Effect level:

5 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 5000 ppm is approximately 200 mg/kg bw/day, assuming food consumption of 20 g/day and body weight of 0.5 kg/rat.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The NOAEL, 5000 ppm, is approximately 200 mg/kg bw/day, assuming food consumption of 20 g/day and body weight of 0.5 kg/rat (ECHA, 2010, Guidance on information requirements and chemical safety assessment, Chapter R.8 -17, after Gold, et.al, 1984 and Paulussen, et al., 1998)

Applicant's summary and conclusion

Conclusions:

Dimethyl terephthalate, a structural analogue of dimethyl isophthalate, was administered to rats in the diet for 13 weeks in a study similar to OECD 408. Doses ranged from 1750 to 20000 ppm. There were no adverse effects on food consumption, clinical signs, gross pathology or histopathology. The NOAEL is 5000 ppm, equivalent to approximately 200 mg/kg body weight/day. Data can be read-across to dimethyl isophthalate from DMTP, based on common functional groups. The substances are isomers. The similarities in structure are likely to apply to metabolites as well, with DMIP breaking down to isophthalic acid, just as DMTP is known to break down to terephthalic acid; these are isomers. Similar structures and similar break-down products for the two substances is the basis for the reading-across of data for this endpoint. This is adequate to fulfill the information requirements of Annex IX, to be the basis for classification and labelling decisions, and for risk assessment.