Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
14 days
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 and only 1 sex tested. Study was conducted by an internal Eastman Kodak Company method developed prior to established guidelines but in accordance with generally accepted scientific principles of the time. No analytical data were provided to verify identity, purity, or stability of the test material or exposure concentrations in the chambers. The results of this study are valid for classification insofar as the conditions of exposure are at least as stringent as modern guidelines.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Five male albino rats per group were exposed to 0 or a mean of 0.0718 mg/L of di (2-ethylhexyl) terephthalate by inhalation 5 days/week 6 hours/day for 10 consecutive weekdays over a 14-day period. Three days after the last inhalation exposure, blood was taken for hematology and clinical chemistry evaluations, animals were weighed and euthanized, a gross necropsy was performed, organs were weighed, and a microscopic analysis was performed.
GLP compliance:
no
Remarks:
Study conducted prior to GLPs
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
-Test substance (as cited in report): Bis (2-ethylhexyl) terephthalate
-The identity, purity, and stability of the test substance were not reported by the testing laboratory.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Test animals:
-Sex: male
-Age at study initiation: 8 - 9 weeks
-Weight at study initiation: 232 - 254 g
-Housing: group-housed (5 animals per cage)
-Diet: ad libitum during non-exposure periods
-Water: ad libitum during non-exposure periods

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
6.0 L/min of airflow was passed through a gas washing bottle containing undiluted di (2-ethylhexyl) terephthalate that was heated on a water bath at 95 °C; chamber temperature was 27 °C. This created a vapor concentration range of 0.0463-0.0926 mg/L with an average 10-day inhalation exposure of 0.0718 mg/L. Control animals were exposed to filtered air in a similar manner as the test substance exposed animals. No test substance contaminants were found in the control chamber during the study.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 hours per day
Frequency of treatment:
5 days/week over a 14-day period
No. of animals per sex per dose:
5 males per dose
Control animals:
yes, concurrent no treatment
Details on study design:
Five male albino rats per group were exposed to 0 or a mean concentration of 0.0718 mg/L of di (2-ethylhexyl) terephthalate by inhalation 5 days/week 6 hours/day for 10 consecutive weekdays over a 14 day period. Three days after the last inhalation exposure, blood was taken for hematology and clinical chemistry evaluations, animals were weighed and euthanized, a gross necropsy was performed, organs were weighed, and a microscopic analysis was performed.

Examinations

Observations and examinations performed and frequency:
-Examinations: Animals were observed daily for signs of toxicity.

-Body Weights: Body weights were measured on Days 0, 5, 8, 12, and 15.

-Feed Consumption: Feeders were not weighed.
Sacrifice and pathology:
-Study Termination: The rats were fasted overnight prior to necropsy. Blood was collected from the tail vein at the time of necropsy for hematology and clinical chemistry analysis. The animals were euthanized with an intraperitoneal injection of pentobarbital sodium and necropsied three days after the last exposure.

-Clinical Chemistry Tests: Serum glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), alkaline phosphatase (AP), and urea nitrogen (UN).

-Hematology Tests: Hemoglobin concentration, white blood cell count, differential white blood cell count, and hematocrit.

-Organ Weights: Liver and kidney.

-Tissues Collected and fixed in 10% buffered formalin: Trachea, lungs, heart, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, pancreas, liver, kidneys, urinary bladder, thyroid, parathyroid, thymus, adrenal glands, spleen, mesenteric lymph nodes, femoral bone marrow, brain, testes, and gross lesions.

-Tissues Collected and fixed in Zenker's fluid: Eyes

-Histopathology: All collected tissues from the treated and control groups were examined microscopically.
Statistics:
Mean values were calculated for body weight, organ weight, hematology, and clinical chemistries. All mean data were evaluated using a computer-generated one-way analysis of variance (ANOVA).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
-Mortality: No mortality was observed during the study.

-Clinical abnormalities: No treatment-related clinical abnormalities were reported.

-Body Weight: Mean body weights were comparable among groups throughout the study.

-Hematology: All hematology parameters were comparable among groups.

-Clinical Chemistry: All clinical chemistry parameters were comparable among groups.

-Gross Pathology: Minor non-specific changes were found in control and treated animals including focal mononuclear cell infiltrates in the heart, liver, and kidney, pericholangitis, focal interstitial nephritis, focal dilation of renal tubules and bilateral testicular atrophy with interstitial cell hyperplasia. Minor changes fround in treated animals only but were not of any toxicological significance included localized fibrosis of the splenic capsule and foci of hypospermatogenesis. Changes were noted in the trachea and lungs of treated and control animals with no clear evidence of a test-substance related effect. These changes included minor mononuclear infiltrates in the trachea, peribronchial lymphoid hyperplasia, perivascular mononuclear cell infiltration, peribronchiole mononuclear cell infiltration, bronchiolitis (minor), focal increases in alveolar macrophages, alveolitis charachterized by the presence of individual or small groups of alveolar macrophages and localized interstitual mononuclear cell infiltrates with or without fibrosis. There were no treatment-related gross lesions noted.

-Organ Weights: All mean organ weights were comparable among groups.

-Histopathology: There were no treatment-related microscopic lesions noted.

Effect levels

Dose descriptor:
NOEL
Effect level:
0.072 other: mg/L air
Sex:
male
Basis for effect level:
other: No compound related effects were found after inhalation exposure to di (2-ethyhexyl) terephthalate at the highest concentration that could be generated by heating the test substance to 95 °C.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a subacute inhalation toxicity study, 5 male rats each were exposed to 0 or a mean concentration of 0.0718 mg/L (daily concentrations: 0.0463-0.0926 mg/L) di (2-ethylhexyl) terephthalate 6 hours/day, 5 days/week for 2 weeks. Under the conditions of this study, no deaths occurred and no signs of toxicity were evident during the study. The no-observed-effect-level (NOEL) for inhalation exposure to di (2-ethylhexyl) terephthalate is 0.0718 mg/L. Based on the results of this study, di (2-ethylhexyl) terephthalate is not classified for “Specific Target Organ Toxicity – Repeat Exposure” according to GHS.
Executive summary:

In a subacute inhalation toxicity study, 5 male rats each were exposed to 0 or a mean concentration of 0.0718 mg/L di (2-ethylhexyl) terephthalate 6 hours/day, 5 days/week for 2 weeks. Under the conditions of this study, no mortality was observed, clinical observations occurred with equal frequency between the control and test substance exposed animals and hematology and clinical chemistry were within the normal ranges for both groups. There were no significant treatment-related gross or microscopic effects observed at necropsy. Based on the results of this study, di (2-ethylhexyl) terephthalate presents a low inhalation toxicity hazard under conditions of normal use. The no-observed-effect-level (NOEL) for inhalation exposure to di (2-ethylhexyl) terephthalate following repeated exposure for 6 hours/day is greater than 0.0718 mg/L.