Bis(hydroxyethyl) terephthalate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

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: inhalation

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:

SIDS reported (2) reliable with restrictions; Reliability was decreased due to inability to measure test particle size

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

fixed concentration 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:

At initiation of exposure rats weighed an average of 198 g (M) and 167 g (F).

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Remarks:

Animals were rinsed in warm water after exposure to remove test material from skin.

Vehicle:

air

Remark on MMAD/GSD:

Technical difficulties prevented sizing of the particulate test material and the protocol-desired exposure concentration of 5 mg/l for 4 hours. Thus, animals underwent only a 2 hour exposure to 2.02 mg/l.

Details on inhalation exposure:

Animals were exposed to a single 2.02 mg/l concentration of test material as a particulate aerosol for two hours. A time-weighted average concentration was determined by gravimetric analysis. Exposure occurred in 68.2 L glass chambers at a temperature of 21°C and relative humidity of 40%.

Body weights were assessed at time of exposure and on Days 7 and 14.

Animals were observed daily for 14 days at which time they were killed and necropsied.

Duration of exposure:

2 h

Concentrations:

2.02 mg/l

No. of animals per sex per dose:

5/sex

Control animals:

not specified

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.02 mg/L air

Based on:

test mat.

Exp. duration:

2 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.012 other: mmol/L

Based on:

test mat.

Exp. duration:

2 h

Mortality:

No deaths were noted in either sex.

Clinical signs:

diarrhoea

Remarks:

Clinical signs consisted of: normal (M1/5; F 3/5); diarrhea (M :3/5); redness around nose (M 4/5; F 1/5); wet inguinal fur (F 1/5); discolored inguinal fur (M 3/5; F 2/5); discolored abdominal fur (F 1/5); and abdominal hair loss (F 1/5).

Body weight:

Mean body weights increased during the study

Gross pathology:

Alterations noted during gross necropsy consisted of: normal (M 3/5; F 4/5); dark lungs (M 1/5); and enlarged mandibular lymph node (M 1/5; F 1/5).

Interpretation of results:

GHS criteria not met

Conclusions:

The terephthalic acid 2 hour LC50 (rats) > 2.02 mg/L

Cross-reference 3

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: inhalation

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 403 (Acute Inhalation Toxicity)

GLP compliance:

not specified

Specific details on test material used for the study:

99% pure

Species:

mouse

Strain:

CD-1

Remarks:

Crl:CD-1 (ICR)BR

Sex:

female

Details on test animals or test system and environmental conditions:

Animals were kept on a 12-hr photoperiod (0530-1730h for light phase) and room temperature and relative humidity were continuously recorded.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

other: nose-only or whole-body

Vehicle:

water

Mass median aerodynamic diameter (MMAD):

2.6 µm

Geometric standard deviation (GSD):

1.7

Remark on MMAD/GSD:

The particle size distribution was similar in all exposure groups.

Details on inhalation exposure:

Nose-only exposure:
Polycarbonate and stainless-steel, rectangular in shape, and accommodated up to 60 mice. Air flowed horizontally through two separate exposure channels (upper and lower) where the noses of the mice protruded into each channel. A Teflon nose seal prevented leakage of air (or test material) from the exposure channel.
One- or two-barrel Laskin nebulizers were used to generate the aerosol. The operating pressures of the nebulizers were 3, 6.5 or 5 psig for the 500, 1000, or 2500 mg/m³ exposure concentrations, respectively.

Whole-body exposure
The aerosol was generated using a recirculating system which contained two four-barrel Laskin nebulizers placed inside glass round-bottom flasks. Filter and compressed air was supplied to each nebulizer causing the test item to be aspirated into atomization tubes and generated as a liquid aerosol. The liquid aerosol was then introduced into the top of the exposure chamber where it was diluted to the final concentration and dispersed through the chamber by filtered and conditioned supply air. The operating pressure for each nebulizer was 32 psig.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Gas chromatograph equipped with a flame ionization detector was used to measure the test item concentrations of the impinger solutions with calibration of the GC by injection of standard solutions of test item in distilled water.

Duration of exposure:

6 h

Remarks on duration:

This was a repeated dose study, the animals were exposure 6hr/day from gestation day 6 through 15.

Concentrations:

Nose-only: 500, 1000, 2500 mg/m³

Whole-body: 2100 mg/m³ as the target, with 2600 mg/m³ as the actual concentration achieved

No. of animals per sex per dose:

30 per group

Control animals:

yes

Remarks:

Whole-body exposure as positive control

Details on study design:

Mice were exposed to test item aerosol (MMAD 2.6 ± 1.7 µm) on Gestation Days (GD) 6 though 15, 6hr/day, by nose-only (0, 500, 1000 or 2500 mg/m³) or whole-body exposure (2100 mg/m³, as positive control), 30/group.

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

> 2.5 mg/L air

Based on:

test mat.

Exp. duration:

6 h

Sex:

female

Dose descriptor:

LC50

Effect level:

> 0.04 other: mmol/L

Exp. duration:

6 h

Mortality:

Two out of 30 females died in the control water aerosol nose-only group and six out of 30 females died in the 2500 mg/m³ nose-only group. These females died immediately after placement in the nose-only apparatus, and apparently died from asphyxiation from improper insertion into the nose-only aperture and/or "drowning" from high concentrations of aerosol at the inlet side of the nose-only chamber.

Body weight:

Body weight gain as expected.

Interpretation of results:

GHS criteria not met

Conclusions:

The ethylene glycol 6hr LC50 > 2.5 mg/L

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:

LC50

Effect level:

> 3.09 mg/L air

Exp. duration:

2 h

Effect levels 2

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.012 other: mmol/L

Exp. duration:

2 h

Other findings:

The 2h LC50 for terephthalic acid (202-830-0; 100-21-0) is reported as > 2.02 mg/L (> 0.012 mmol/L)

The 6h LC50 for ethane-1,2-diol (203-473-3; 107-21-1) is reported as > 2.5 mg/L (> 0.040 mmol/L)

Based on a conservative prediction, the 2h LC50 of BHET (959-26-2; 213-497-6) is predicted to be > 3.09 mg/L (> 0.012 mmol/L).

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 2h LC50 of the target substance was predicted to be greater than 0.012 mmol/L or greater than 3.09 mg/L.

Executive summary:

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

 

The acute inhalation toxicity of terephthalic acid was assessed in rats in a GLP-compliant acute inhalation toxicity study. Male and female Sprague-Dawley rats were exposure for 2 hours to a single dose of 2.02 mg/L terephthalic acid and were observed for 14 days. No mortalities were reported. The acute 2h LC₅₀ was reported as > 2.02 mg/L or > 0.012 mmol/L. CD-1 female mice were used to assess the reproductive effects of repeated exposure to ethylene glycol by inhalation. The 6h LC₅₀ of ethylene glycol was > 2.5 mg/L or 0.040 mmol/L. The conservative 2h LC₅₀ of BHET was predicted to be greater than 0.012 mmol/L or greater than 3.09 mg/L.