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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published study.

Data source

Reference
Reference Type:
publication
Title:
Absorption, Distribution and Excretion of Terephthalic Acid and Dimethyl Terphthalate
Author:
Moffitt, A.E., Clary, J.J., Lewis, T.R., Blanck, M.D. and Perone, V.B.
Year:
1975
Bibliographic source:
American Industrial Hygiene Association Journal, 36(8), 633-41 (1975). Publ.: Taylor & Francis. (http://www.informaworld.com/smpp/title~content=t713608243~db=all)

Materials and methods

Objective of study:
other: absorption, distribution and excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Absorption distribution and excretion study.
GLP compliance:
no
Remarks:
older published study, pre-dates GLP

Test material

Reference
Name:
Unnamed
Type:
Constituent
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: Rats and rabbits were used.
Strain:
other: Charles River rats and New Zealand albino rats.
Sex:
male
Details on test animals and environmental conditions:
Adult male Charles River (200-225 g) were used in the oral, intratracheal and dermal studies. Adult male New Zealand albino rabbits (2-3 kg) were used for the eye irritation study.

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 TA or DMT was prepared for oral administration by dissolving the test substance 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 DMT was 20 and 40 mg doses. TA was administered in 40 and 80 mg doses.

For intratracheal, dermal and ocular administration, labelled TA and DMT 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 DMT were used in this study; tracer only, 5 mg and 10 mg.

In the dermal study, doses of TA or DMT were applied in 0.2 mL of vehicle to the unabraded, depilated backs of rats which were divided into two dosage groups. One group of rats received a single dose of 80 mg of TA or DMT; 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.

For the ocular instillation study, the proposed FDA test for eye irritants was followed. Eight albino rabbits were used for each test substance. A single 50 mg dose of radiolabelled TA or DMT 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:
The duration and frequency of the treatment is stated above in the details on exposure.
Doses / concentrations
Remarks:
Doses / Concentrations:
For the ocular administration, a single 50 mg dose was used.
For the dermal administration, a dose of 80 mg was used.
For the oral administration experiment, doses of 0, trace, 20 mg or 40 mg were used.
For the intracheal experiment, the doses used were 0, trace, 5 mg or 10 mg.
No. of animals per sex per dose:
In each group there were five animals for all studies.
Control animals:
yes, concurrent vehicle
Positive control:
There was no positive control used.
Details on study design:
There are no further details to report on the study design. See details on exposure for study design.
Details on dosing and sampling:
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 Mterial Oxidizer,a total combustion furnace which oxidises carbonaceous materials to carbon dioxide, which is subsequently collected for counting in a strong organic base.
Statistics:
No statistical analysis performed.

Results and discussion

Preliminary studies:
No preliminary studies conducted.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In the oral administration test, the data indicated negligible tissue absorption or accumulation of the labelled material in all organs counted for radioactivity.
Intratrachel administration: Less than 1% of the total administered dose was absorbed.
Dermal application: negligible absorption. Lees than 2% of the administered dose was found in the organs.
Ocular application: Less than 0.1% was absorbed.

Intratracheal test: Less than 1% of the total administered dose was absorbed 24 hours after the last injection.
Details on distribution in tissues:
Intratracheal test: the 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.
Details on excretion:
In the oral administration test, 80% of the single dose of DMT was excreted in the urine and feces within 48 hours of administration. DMT 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 DMT 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-DMT appeared in the urine and faeces with a similar pattern of distribution at 48 hours. Poor recoveries of the two higher doses of 14C-DMT were obtained. The poor recoveries of the 5 and 10 mg doses of14C-DMT may be related to inadequate sonication of the DMT emulsion prior to dosing.

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

Ocular administration: 29% of the administered dose of 14C-DMT 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-DMT 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:
No details on metabolites in the paper.

Any other information on results incl. tables

There are no further remarks on the results.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Dimethyl terephthalate 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 of low doses to laboratory animals
Executive summary:

The study was performed in in rabbits and rats to determine the absorption, distribution, and excretion of radioalabelled dimethylterephthalate (DMT) following oral, intratracheal, dermal and ocular administration.

The results of the study indicate the rapid absorption and excretion of DMT with no evidence bioaccumulation in rats, following single or repeated oral or intratracheal administration. Following the dermal application of 80 mg DMT in the rat, absorption of approximately 11% of a single dose and 13% of a repeated dose is reported (based on excretion in the urine and faeces of rats within 10 days). Following application to the conjunctival sac of one eye of eight rabbits, excretion of approximately 33% of a single ocular dose of 50 mg DMT in the urine and feces of rabbits within 10 days is reported. Results suggest that DMT is rapidly absorbed and excreted and that there is no evdience for bioaccumulation.