Dimethyl isophthalate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

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: Scientifically-valid experimental study published in a peer-reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1975

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Radiolabelled substances were administed to rats and rabbits by various routes, and absorption, distribution and excretion were monitored.

GLP compliance:

no

Remarks:

precedes establishment of GLP

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: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Dimethyl terephthalate and terephthalic acid uniformly ring labeled with carbon-14 were obtained from the Malinckrodt Chemical Works, St Louis, Missouri. Unlabelled dimethyl terephthalate and terephthalic acid were obtained from Matheson Scientific Company, Cincinnati, Ohio.

Radiolabelling:

yes

Remarks:

uniformly ring labeled with carbon-14

Test animals

Species:

other: rat and rabbit

Strain:

other: Sprague-Dawley (Charles River) and New Zealand white

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Weight at study initiation: rats: 200-225 g, rabbits: 2-3 kg
- Fasting period before study: no data

Administration / exposure

Route of administration:

other: oral gavage, intratracheal, dermal and ocular

Vehicle:

other: peanut oil for oral administration; 1% solutions of Triton X 100 in distilled water were prepared for intratracheal, dermal and ocular administration.

Details on exposure:

Labelled dimethyl terephthalate (DMTP) and its break-down product, terephthalic acid (TA), were prepared for oral administration by dissolving the test substances in peanut oil. Groups of five rats each received a single oral dose by gastric intubation or on alternate days for 10 consecutive days (five doses). The levels of labelled DMTP was 20 and 40 mg doses. TA was administered in 40 and 80 mg doses.

For intratracheal, dermal and ocular administration, labelled TA and DMTP were prepared in 1% solutions of Triton X-100 in distilled water. In the intracheal study, groups of five rats each received either a single dose or multiple doses on alternate days for 10 consecutive days. The following levels of TA or DMTP were used in this study; tracer only, 5 mg and 10 mg.

In the dermal study, doses of TA or DMTP were applied in 0.2 mL of vehicle to the unabraded, depilatated backs of rats which were divided into two dosage groups. One group of rats received a single dose of 80 mg of TA or DMTP; the remaining group received the same dose on alternate days for 10 consecutive days (five doses). After dosing, the treated area of the back was covered with a gauze patch which was allowed to remain in place for the duration of the single dosage study and was removed only for dosing during the multiple dose study.

Eight albino rabbits were used for each test substance in the ocular exposure study. A single 50 mg dose of radiolabelled TA or DMTP was instilled into the conjunctival sac of one eye of each rabbit. Five animals (Group 1) from each group were exposed to the test substance for five minutes and then the eyes were washed copiously with distilled water and examined. Group II (three animals) received a 24 hour exposure to the test substance and the eyes were then washed and examined. All rabbits were sacrificed 10 days after dosing.

Duration and frequency of treatment / exposure:

For Oral: once and also 5 doses on alternative days for 10 days
For Dermal: once and also 5 doses on alternative days for 10 days
For Intratracheal: once and also 5 doses on alternative days for 10 days
Intraocular: once with washing at either 5 minutes or 24 hours

Doses / concentrations

Remarks:

Doses / Concentrations:
For the oral administration experiment, doses of 0, trace, 20 mg or 40 mg were used
For the dermal administration, a dose of 80 mg was used
For the intracheal experiment, the doses used were 0, trace, 5 mg or 10 mg
For the ocular administration, a single 50 mg dose was used

No. of animals per sex per dose / concentration:

5 male animals/dose (3 in Group II of the ocular exposure experiment)

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

no

Details on study design:

After dosing, animals were housed in metabolism cages for collection of urine and feces. A fine mesh screen was used to separate urine and faeces in each case.

On the tenth day, all rats were sacrificed. The following organs were removed; liver, lungs, heart, kidneys, spleen, femur (not taken in case of ocular instillation study), adrenal, pancreas, testes and brain. Soft tissues and urine were prepared for carbon-14 counting by dissolution with Soluene. Dried faeces, bone, skin and dermal patches were prepared for counting with the Beckman Biological Material Oxidizer,a total combustion furnace which oxidises carbonaceous materials to carbon dioxide, which is subsequently collected for counting in a strong organic base.

Statistics:

mean values of groups

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

In the oral administration test, the data indicated that both DMTP and TA were rapidly absorbed. Both DMTP and TA were absorbed and eliminated.
Intratracheal administration: Less than 1% of the total administered dose was absorbed.
Dermal application: negligible absorption. Less than 2% of the administered dose was found in the organs.
Ocular application: Less than 0.1% was absorbed.

Details on distribution in tissues:

After oral administration, there was negligible tissue distribution or accumulation of the labelled DMTP and TA in all organs counted for radioactivity.
Intratracheal test: 1% absorbed was found in the lungs and tracheal lymph nodes. Negligible radioactivity (<0.1%) was detected in all other organs assayed.
Dermal application: the absorbed amount was found mainly in the liver.
Ocular administration: Negligible radioactivity (<0.1%) was detected in all other organs assayed.

Details on excretion:

In the oral administration test, over 80% of the single dose of DMTP was excreted in the urine and feces within 48 hours of administration. DMTP was predominantly excreted in the urine of rats and less than 10% of the administered dose appeared in the faeces. Repeated oral dosing with labelled DMTP resulted in a similar pattern of excretion. After dosing on alternate days for 10 days (five doses) greater than 89% of the total administered dose was recovered in the urine and faeces 24 hours after the last administration.

Intratracheal test: Approximately 62% of a tracer dose of 14C-DMTP appeared in the urine and faeces with a similar pattern of distribution at 48 hours. Poor recoveries of the two higher doses of 14C-DMTP were noted. The poor recoveries of the 5 and 10 mg doses of 14C-DMTP may be related to inadequate suspension of the DMTP emulsion or difficulties in dosing.

Dermal application: 13% of the administered dose of 14C-DMTP was excreted following repeated dermal administration on alternate days for 10 days. 11% of the administered dose of 14C-DMTP was recovered in the urine and faeces within 10 days following a single dermal application.

Ocular administration: 29% of the administered dose of 14C-DMTP was recoverd in the urine of the rabbits receiving a five minute exposure and approximately 37% of the administered dose was excreted by rabbits receiving a 24-hour exposure. Faecel excretion of 14C-DMTP was minimal (<2%) in this study and may be attributable to urine contamination. Excretion of the test compound was greater in animals receiving a 24 hour ocular exposure.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

Solvent extraction of TA and DMTP from urine and faeces revealed that the major portion of radioactivity was in the water-soluble fraction. These data are consistent with extensive metabolism of these substances to water-soluble metabolites.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

DMTP and TA are bioavailable after all routes of exposure examined in this study. The substances are rapidly excreted from the body, and there is no evidence of bioaccumulation.

Any other information on results incl. tables

Recovery of the higher doses of DMTP and TA (less than 1%) via intratracheal administration was poor, and this prevents conclusions on distribution and excretion from being drawn. This is likely due to poor suspension of the material in Triton X/water vehicle, poor sampling of the suspension, poor administration of the dose as plugging of the injection needle was observed, or relex thoracic expulsion of the dose by the animals shortly after administrtion.. Intratracheal exposure to high concentrations of DMTP is likely not a relevant route of administration under controlled conditions of the workplace.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Dimethyl terephthalate (DMPT) is rapidly absorbed and excreted. No significant quantities of the compound accumulate in the tissues following single or repeated oral, intratracheal and dermal administration or single ocular administration to laboratory animals. 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.  This is adequate to fulfill the information requirements of Annex IX, to be the basis for classification and labelling decisions, and for risk assessment.