Bis(hydroxyethyl) terephthalate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of 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:

accepted calculation method

Justification for type of information:

The basis for this read-across approach is that the target substance is expected to undergo transformation into terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1). The toxicity of the metabolites will accurately predict the toxicity of the bis(2-hydroxyethyl)terephthalate (BHET; 959-26-2; 213-497-6). Refer to the JUSTIFICATION FOR READ-ACROSS OF TOXICOLOGICAL INFORMATION in Section 13 of this dossier for further details.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Cross-reference 2

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

SIDS reported (1) reliable without restriction

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

Terephthalic acid was supplied by the Amoco Corporation. Purity was not noted but typically exceeds 99%.

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

At initiation of exposure rabbits were about 3 months of age and weighed an average of 2.59 kg (M) and 2.45 kg (F).

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Remarks:

neat powder

Details on dermal exposure:

Prior to application, the backs were shaved and moistened with water. A single dose of 2000 mg/kg test material (a neat powder) was applied on the back and covered with an occlusive wrap. Animals were observed daily for 14 days at which time they were killed and necropsied.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5/sex

Control animals:

not specified

Details on study design:

At initiation of exposure rabbits were about 3 months of age and weighed an average of 2.59 kg (M) and 2.45 kg (F). Prior to application, the backs were shaved and moistened with water. A single dose of 2000 mg/kg test material (a neat powder) was applied on the back and covered with an occlusive wrap. Body weights were assessed at dosing, and on Days 7 and 14. Animals were observed daily for 14 days at which time they were killed and necropsied.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 12 other: mmol/kg bw

Based on:

test mat.

Mortality:

none

Gross pathology:

No alterations were noted during gross necropsy.

Other findings:

Mean body weights increased during the study. No alterations were noted during gross necropsy. The only clinical signs noted consisted of an erythema at the application site immediately after unwrapping in 2/5 males and 4/5 females. All animals appeared normal by Day 4.

Interpretation of results:

GHS criteria not met

Conclusions:

The terephthalic acid rabbit dermal LD50 is > 2000 mg/kg bw

Cross-reference 3

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

not specified

Test type:

other: dermal reproduction study with three dose levels

Limit test:

no

Specific details on test material used for the study:

Purity: 100%

Species:

mouse

Strain:

CD-1

Remarks:

Crl:CD-1 (1CR)BR

Sex:

female

Details on test animals or test system and environmental conditions:

Animals were kept on a 12-hr photoperiod (0530 - 1730 hr for light phase) and room temperature and relative humidity were continuously recorded.
Females were 39 days old upon arrival

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

Females were exposed to the test item or the vehicle control on GD 6 through 15.
For cutaneous application, the dorsum (approximately 3 x 3 cm, below the scapulae caudal to the neck) was clipped and shaved prior to the first dosing day and as needed throughout the dosing period.
Dosing solutions were stirred on a magnetic stirrer and then 100 µL was administered from an automatic pipettor onto the shaved dorsum of each mouse. The application site was then occluded with sterile gauze.
The restrainer units with the dosed animals were placed in polycarbonate shoebox cages for 6 hours, the duration of the daily administration period, during which time food and water were withheld. At the end of the exposure period, the tape and gauze were gently removed from each animal and the application site was gently washed with water and sterile gauze.

Duration of exposure:

6 hours

Doses:

0.0%, 12.5%, 50%, 100.0%
approximately 0, 404, 1677, and 3549 mg/kg bw/day

No. of animals per sex per dose:

30/dose

Control animals:

yes, concurrent vehicle

Details on study design:

This study was a repeated-dose developmental study were route of administration was dermal.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 3 549 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 57.2 other: mmol/kg bw

Based on:

test mat.

Mortality:

No mortality was reported in any dose group

Other findings:

There was no significant difference in material weight gain in any group.

Interpretation of results:

GHS criteria not met

Conclusions:

The ethylene glycol acute dermal LC50 is > 3549 mg/kg bw.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Bis(hydroxyethyl) terephthalate

EC Number:

213-497-6

EC Name:

Bis(hydroxyethyl) terephthalate

Cas Number:

959-26-2

Molecular formula:

C12H14O6

IUPAC Name:

bis(hydroxyethyl) terephthalate

Test material form:

solid

Specific details on test material used for the study:

Bis(2-hydroxyethyl) terephthalate value is read-across from supporting terephthalic acid (202-830-0; 100-21-0) and ethane-1,2-diol (203-473-3; 107-21-1) data

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 061 mg/kg bw

Effect levels 2

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 12 other: mmol/kg bw

Other findings:

The dermal LD50 for terephthalic acid (202-830-0; 100-21-0) is reported as > 2000 mg/kg bw (> 12.0 mmol/kg bw)

The dermal LD50 for ethane-1,2-diol (203-473-3; 107-21-1) is reported as > 3549 mg/kg bw (> 57.2 mmol/kg bw)

Based on a conservative prediction, the dermal LD50 of BHET (959-26-2; 213-497-6) is predicted to be > 3061 mg/kg bw (> 12.0 mmol/kg bw).

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance; therefore, the acute dermal LD50 of the target substance was predicted to be greater than 12.0 mmol/kg bw or greater than 3061 mg/kg bw.

Executive summary:

Information on the source substances is considered to be directly applicable to an equivalent molar amount of the target substance.

 

The acute dermal toxicity of terephthalic acid was assessed in New Zealand White rabbits in a GLP-compliant acute dermal toxicity study. Male and female rabbits were exposure 2 000 mg/kg bw terephthalic acid under occlusive conditions. The animals were observed for a total of 14 days. No mortality was reported and there were no alterations noted during gross necropsy. The dermal LD₅₀ was reported as > 2 000 mg/kg bw or greater than 12.0 mmol/kg bw. CD-1 female mice were used to assess the reproductive effects following repeated exposure to ethylene glycol by dermal exposure. The mice were repeatedly dermally exposed to various concentrations of ethylene glycol. The ethylene glycol was washed off after 6 hours of exposure. No deaths were reported during this repeated-dose study. Based on the highest concentration tested, the acute dermal LD₅₀ was greater than 3 549 mg/kg bw or greater than 57.2 mmol/kg bw. The conservative acute dermal LD₅₀ of BHET was predicted to be greater than 12.0 mmol/kg bw or greater than 3 061 mg/kg bw.