Bis(hydroxyethyl) terephthalate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

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:

read-across: supporting information

Cross-reference 2

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

Reported as reliability (1) reliable without restriction within SIDS

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

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:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age at study initiation: 9 weeks
Weight at study initiation: Average of 310 g (M) and 183 g (F)

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

A single dose of 5000 mg/kg test material was diluted with water to form a 50% w/v suspension. This was administered by oral gavage at a rate of 10 ml/kg.

Doses:

> 5,000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

Duration of observation period following administration: 14 days
Frequency of observations and weighing: Animals were observed daily for clinical signs. Body weights were assessed at dosing, and on Days 7 and 14.
Necropsy of survivors performed: yes
Other examinations performed: clinical signs, body weight

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 30.1 other: mmol/kg bw

Based on:

test mat.

Mortality:

No deaths were noted in either sex.

Clinical signs:

other: Clinical signs consisted of diarrhea (M 5/5; F 5/5), redness around nose (M 3/5; F 2/5) and discolored inguinal fur (M 4/5; F 1/5). Signs diminished in most animals by 48 hours, and all were normal at study termination.

Body weight:

other body weight observations

Remarks:

Mean body weights increased during the study.

Other findings:

No alterations were noted during gross necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral terephthalic acid LD50 in rats is greater than 5 g/kg, with some rats exhibiting clinical signs of diarrhea, redness around nose and discolored inguinal fur.

Cross-reference 3

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: oral

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

Remarks:

The work of this group pre-dates range finding toxicity guidelines and provided much of the basis for their development. Their results are cited by many subsequent authoritative review bodies and are often found in SIDS and SIAR documents via secondary references. Therefore, these results are deemed reliable.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

The work of this group pre-dates range finding toxicity guidelines and provided much of the basis for their development. Their results are cited by many subsequent authoritative review bodies and are often found in SIDS and SIAR documents via secondary references. Therefore, these results are deemed reliable.

GLP compliance:

no

Remarks:

pre-dates GLP

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Reported as Ethylene glycol

Species:

rat

Strain:

other: albino Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 90 - 120 g
- Diet: Purina chows, supplemented by fresh vegetables
- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: maximal concentration 500 mg/mL

MAXIMUM DOSE VOLUME APPLIED: Individual dose levels were not reported for any of the substances tested including the test substance considered herein. According to the authors, the highest dose level which could safely be hold at one time by the animal was just over 10% of the animal’s bodyweight, corresponding to approx. 50 g/kg bw, when a substance was administered as a 50% solution. This is equivalent to a dose volume of 100 mL/kg bw.
Furthermore, it was reported that in most cases 10 animals were dosed to determine the toxicity of a particular dosage and enough dosages were given to include those at which no mortality occurred and those at which all tested animals died.
The test substance was administered as a 50% solution and based on the information above and the resulting LD50 value, it appears unlikely that the test substance could have been administered at a dose volume > 100 mL/kg bw.
It is therefore assumed that the maximum dose volume applied was 100 mL/kg bw corresponding to a maximum dose level of 50000 mg/kg bw.

Doses:

Not specified (presumably up to 50000 mg/kg bw)

No. of animals per sex per dose:

ca. 10

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

The data were calculated by the method of probits, described by Bliss C.I. (1935. The calculation of the dosage-mortality curve. Ann. Appl. Biol. 22:134-167).

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

8 540 mg/kg bw

Based on:

test mat.

95% CL:

7 310 - 9 990

Sex:

male

Dose descriptor:

LD50

Effect level:

137.6 other: mmol/kg bw

Based on:

test mat.

Mortality:

Mortality data were summarised for all substances tested. Therefore, no substance specific data were reported.
According to the authors, most deaths occurred within the first 48 h post-dose, but all deaths within 14 days post-administration were taken into account for calculation of LD50 values. In some glycols, death was delayed about a week.

Clinical signs:

other: Fatal or near fatal doses of the glycols and their esters produced no narcosis but varying degree of sluggish depressed functioning.

Gross pathology:

Gross pathology findings were summarised for all substances tested. According to the authors, all doses caused some degree of irritation of the digestive tract. The primary target organ was the kidney; blood in urine and free blood beneath the capsule were seen at the highest dosages. The liver was less affected, but orange or reddish bile was often observed.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral ethylene glycol LD50 (rat) is 8540 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

Test animals

Species:

rat

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 3 420 mg/kg bw

Effect levels 2

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 26.9 other: mmol/kg bw

Other findings:

The LD50 for terephthalic acid (202-830-0; 100-21-0) is reported as > 5000 mg/kg bw (> 30.1 mmol/kg bw)

The approximate lethal human dose for ethane-1,2-diol (203-473-3; 107-21-1) is reported as approximately 1670 mg/kg bw (~ 26.9 mmol/kg bw)

Based on a conservative prediction, the LD50 of BHET (959-26-2; 213-497-6) is predicted to be ~ 3420 mg/kg bw (~ 26.9 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 LD50 of the target substance was predicted to be approximately 26.9 mmol/kg bw or approximately 3420 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 oral toxicity of terephthalic acid was assessed in rats in a GLP-compliant acute oral toxicity study. Male and female Sprague-Dawley rats were exposure to a single dose of 5 000 mg/kg bw terephthalic acid and were observed for 14 days. No mortalities were reported, and no alterations were noted during gross necropsy. The acute oral LD₅₀ was reported as > 5 000 mg/kg bw or > 30.1 mmol/kg bw. Albion Wistar rats were used to assess the acute oral toxicity of ethylene glycol in a study that predates GLP. The acute oral LD₅₀ of ethylene glycol was reported as 8 450 mg/kg bw or 136.1 mmol/kg bw. However, clinical experience has identified ethylene glycol as more acutely toxic for humans than for laboratory animals following ingestion. The approximate lethal oral dose of 95% ethylene glycol is 1.5 ml/kg (1 670 mg/kg bw; 26.9 mmol/kg bw); therefore, the LD₅₀ of the target substance was predicted to be approximately 26.9 mmol/kg bw or approximately 3 420 mg/kg bw.