Bis(2-ethylhexyl) terephthalate

Endpoint summary

Description of key information

The single dose oral LD50 in rats was greater than 5000 mg/kg bw.

The dermal LD50 in guinea pigs was > 20.0 mL/kg bw (equivalent to 19,680 mg/kg bw).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 days

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Remarks:

Reliable without restriction; study followed GLPs and TSCA FHSA Regulations (1979): 16 CFR Part 1500.40 (Hazardous Substances and Articles, Administration and Enforcement Regulations).

Qualifier:

according to guideline

Guideline:

other: TSCA FHSA Regulations (1979): 16 CFR Part 1500.40 (Hazardous Substances and Articles, Administration and Enforcement Regulations)

Deviations:

not specified

GLP compliance:

yes

Limit test:

yes

Species:

rat

Strain:

other: CD(SD)BR VAF/Plus

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals:
-Sex: male and female
-Age at study initiation: 7-8 weeks (males); 8-9 weeks (females)
-Weight at study initiation: 211-241 g (males); 202-218 g (females)
-Housing: individually housed in suspended, stainless-steel wire mesh cages
-Diet: Agway Prolab certified Animal Diet (pellets)
-Water: Monroe County, NY local water ad libitum
-Method of animal distribution: randomly assigned to the study based on a computer-generated list

Environmental Conditions:
-Temperature: 68 - 72 °F
-Humidity: 44-55% relative humidity
-Photoperiod: 12 hours light/12 hours dark

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Animals were given a single dose of the neat test substance.

Doses:

5000 mg/kg bw (single dose)

No. of animals per sex per dose:

5 rats/sex

Control animals:

no

Details on study design:

Animals were observed for signs of toxicity three times on the day of dosing, and daily for two weeks thereafter. Body weights were measured on Days 0, 7, and 14. All animals were necropsied at the completion of the 14-day observation period.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

No mortality was observed during the study.

Clinical signs:

other: Clinical abnormalities were limited to oily, unkempt inguinal hair for all animals on Days 1 and 2 of the study, and yellow discolored inguinal hair for two female rats on Day 1.

Gross pathology:

No treatment-related changes were observed at necropsy.

Other findings:

In the absence of significant gross organ lesions, no tissue was collected for microscopic examination.

Interpretation of results:

study cannot be used for classification

Conclusions:

Under conditions used in this study, di (2-ethylhexyl) terephthalate was practically nontoxic by the oral route in rats. The single dose oral LD50 in rats was greater than 5000 mg/kg bw.

Based on an acute oral LD50 value of greater than 5000 mg/kg bw in rats, di (2-ethylhexyl) terephthalate is not classified for classification and labeling for acute lethality by the oral route under GHS.

Executive summary:

In an acute oral toxicity study, five rats per sex were administered a single dose of di (2-ethylhexyl) terephthalate by oral gavage at a dose level of 5000 mg/kg bw. The rats were observed for mortality and adverse clinical signs for a period of 14 days. No mortality was observed in the study. Clinical signs of toxicity were limited to oily, unkempt inguinal hair for all animals on Days 1 and 2 of the study, and yellow discolored inguinal hair for two female rats on Day 1. No other clinical abnormalities were noted throughout the study. All rats gained weight over the 14-day observation period. Based on the results of this study, the LD50 per os of di (2-ethylhexyl) terephthalate is greater than 5000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

study followed GLPs and TSCA FHSA Regulations and OECD guidelines

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24-hour exposure followed by 14 day observation period

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study conducted prior to introduction of Good Laboratory Practices; data from a summary report; limited number of animals. Study was conducted by an internal Eastman Kodak Company method, developed prior to established guidelines. The results of this study are valid for classification insofar as the conditions of exposure are at least as stringent as modern guidelines.

Qualifier:

no guideline followed

Deviations:

not specified

Principles of method if other than guideline:

Method is an in vivo study using three guinea pigs. Following depilation of the abdomen of each animal, a single dose of the test substance is applied under an occlusive wrap for 24 hours. Animals are observed following removal of the cuff, and on Days 7 and 14. In addition to observations for mortality, dermal reactions and weight changes were also recorded.

GLP compliance:

no

Remarks:

Study conducted prior to GLPs

Test type:

other: internal Eastman Kodak method

Limit test:

no

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Test animals:
-Weight at study initiation: 535 - 575 g

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Following depilation of each animal's abdomen, a single dose of 5.0, 10.0, or 20.0 mL/kg bw of the test substance was applied under an occlusive cuff and wrap. This is equivalent to 4920, 9840 or 19,680 mg/kg bw based on the density (0.984 g/cm3) of the undiluted test material. After a 24-hour exposure period, the cuffs and wrappings were removed.

Duration of exposure:

24 hours

Doses:

5.0, 10.0, and 20.0 mL/kg bw

No. of animals per sex per dose:

1 animal/dose (sex not specified)

Control animals:

no

Details on study design:

Three guinea pigs (sex, age, and initial weights not provided) were used. Following depilation of the guinea pig abdomens, a single dose of 5.0, 10.0, or 20.0 mL/kg bw of the test substance was applied under an occlusive wrap prepared from a pad of gauze held in place with an impervious cuff made of rubber dental dam material. The cuff was wrapped securely around the torso of the guinea pig and held in place with non-irritating tape. Animals were exposed for 24 hours, then the cuffs were removed. Animals were observed following removal of the cuff, and on Days 7 and 14. In addition to observations for mortality, dermal reactions were also noted. Guinea pigs were weighed prior to administration of the test substance and at termination of the 14-day observation period.

Statistics:

not performed

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 20 mL/kg bw

Mortality:

None

Clinical signs:

other: No signs of test material absorption or systemic toxicity were noted during the study. Signs of irritation at the application site were limited to moderate to gross edema (24 hours) and slight desquamation (7 and 14 days).

Gross pathology:

not performed

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

Three guinea pigs were exposed to the test substance at dose levels of 5, 10, or 20 mL/kg bw for 24 hours under an occlusive cuff. The dermal LD50 in guinea pigs was > 20.0 mL/kg bw (equivalent to 19,680 mg/kg bw).

Based on an acute dermal LD50 value of greater than 20 mL/kg bw in guinea pigs, di (2-ethylhexyl) terephthalate is not classified as a toxicant for classification and labeling for acute lethality by the dermal route according to GHS.

Executive summary:

In an acute dermal toxicity study, 3 guinea pigs were exposed for 24 hours under occlusive contact to 5, 10 or 20 mL/kg bw of di (2-ethylhexyl) terephthalate. Under the conditions of this study, no deaths occurred and the dermal LD50 was considered to be > 20.0 mL/kg bw. No signs of skin absorption or systemic toxicity were evident during the study. At the application sites, signs of irritation caused by the solvent included moderate to gross edema at 24 hours, and slight desquamation at both 1 and 2 weeks after test substance administration. A body weight gain was noted in all animals over the 2-week observation period. Based on the results of this study, di (2-ethylhexyl) terephthalate presents a low toxicity hazard but may cause significant irritation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

19 680 mg/kg bw

Quality of whole database:

key study.

Additional information

Oral Toxicity

 The acute toxicity of di (2-ethylhexyl) terephthalate is well understood. In an acute oral toxicity study conducted according to Good Laboratory Practices (GLPs) and US TSCA FHSA regulations, di (2-ethylhexyl) terephthalate had an acute oral LD50 value of > 5000 mg/kg bw in male and female rats. No mortality was observed in the study, clinical signs were minimal, all animals gained weight during the study, and no treatment-related changes were observed at gross necropsy. Other lesser studies in rats and mice support the acute oral LD50 value. In those studies no deaths, no adverse clinical signs, and no adverse effects on weight gain were observed in animals administered up to 3200 mg/kg bw of di (2-ethylhexyl) terephthalate by the oral route. Based on these data, di (2-ethylhexyl) terephthalate is demonstrated to be a low order of acute toxicity following ingestion.

  

Dermal Toxicity

  

The acute dermal toxicity of di (2-ethylhexyl) terephthalate is well understood. Although an acute dermal toxicity study conducted according to OECD Guideline 402 was not identified, a non-guideline study conducted by a credible testing laboratory according to acceptable scientific methods of the time was available for review. In this study, doses of 5, 10 or 20 mL/kg bw (equivalent to 4920, 9840 or 19,680 mg/kg bw) di (2-ethylhexyl) terephthalate were applied to the depilated abdomens of guinea pigs under occluded contact for 24 hours. There were no deaths observed in this study. No signs of test material absorption or systemic toxicity were noted during the study and all animals gained weight during the observation period. The dermal LD50 is considered to be > 20 mL/kg bw (19,680 mg/kg bw). Based on the results of this study, di (2-ethylhexyl) terephthalate is considered to present a low acute toxicity hazard for skin contact. Although signs of irritation at the application site were observed, these followed 24-hour occluded contact with large volumes of test material, conditions much more stringent than are used in current guideline irritation studies.

  

Inhalation Toxicity

  

The acute inhalation toxicity of di (2-ethylhexyl) terephthalate is well understood. Although a study conducted according to OECD Guideline 403 was not identified, a subacute non-guideline study conducted by a credible testing laboratory according to acceptable scientific methods of the time was available for review. In this study (provided in detail in the Repeat-Exposure section of this submission), a group of 5 male albino rats was exposed to 0 or 0.0718 mg/L of di (2-ethylhexyl) terephthalate by whole body inhalation 5 days/week, 6 hours/day for 10 days over a 14 day period. Three days after the last exposure, animals were sacrificed, a gross necropsy was performed, organs weighed, and microscopic analysis performed. No deaths, clinical signs, or adverse effects on body weight gains were observed. All hematology and clinical chemistry parameters in exposed animals were comparable to controls. There were no treatment-related gross or microscopic lesions. Based on a No-Observed-Effect-Level of 0.0718 mg/L following repeated 6-hr exposures to di (2-ethylhexy) terephthalate, the LC50(6-hr) is considered to be at least 0.0718 mg/L. This exposure level could only be generated by passing an airflow of 6.0 L/min through a gas washing bottle containing undiluted di (2-ethylhexyl) terephthalate that was heated on a water bath at 95°C. Di (2-ethylhexyl) terephthalate is a liquid at room temperature with a low volatility. Exposure to vapors is unlikely because the vapor pressure is estimated to be 2.85 E-5 hPa at 25°C. Based on the physical properties of di (2-ethylhexyl) terephthalate, the potential for significant inhalation exposure is limited. Based on data from repeated exposure studies, di (2-ethylhexyl) terephthalate is considered to present a low acute toxicity hazard by the inhalation route.

Justification for classification or non-classification

Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for acute toxicity. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate would not be classified for lethality by the oral, dermal, or inhalation routes according to the UN Globally Harmonized System of Classification and Labeling (GHS) or the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) no. 1272/2008. Based on a weight–of-the-evidence assessment, di (2-ethylhexyl) terephthalate is also not classified for “Specific Target Organ Effects – Single Exposure”. No significant clinical signs, body weight changes or gross or microscopic observations to indicate systemic toxicity were observed by any route of exposure.