Registration Dossier

Administrative data

Description of key information

The overall NOEL for the 90-day feeding study was 0.5% in the diet (equivalent to 277 and 309 mg/kg bw/day for males and females, respectively).

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
90 days
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Reliable without restrictions; study was conducted in accordance with GLPs and under methods similar to those described in EPA guideline 799.9310 TSCA 90-Day Oral Toxicity Study in Rodents.
Qualifier:
equivalent or similar to guideline
Guideline:
other: EPA guideline 799.9310 TSCA "90-Day Oral Toxicity Study in Rodents"
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test animals:
-Strain: Sprague-Dawley (CRL: COBS® CD® (SD) BR)
-Source: Charles River Laboratories, Wilmington, MA, USA
-Sex: Male and Female
-Age at receipt: Males: approximately 4 weeks old; Females: approximately 6 weeks old
-Age at study initiation: approximately 6 (males) - 8 (females) weeks old
-Acclimation period: 2 weeks
-Weight at study receipt: Males: 250 ± 50 g
Females: 200 ± 50g
-Housing: Animals were housed 5 per cage in stainless steel wire-mesh cages; males and females were housed on separate racks.
-Diet: Purina Laboratory Rodent Chow 5002 (certified) ad libitum
-Water: Local municipality (Monroe County, NY) ad libitum
-Method of animal identification: Unique metal ear tag and a standardized ear punch
-Method of animal distribution: Computer-generated randomization procedure.
-Quality control animals: On the day of receipt, 3 animals/sex were randomly selected from each of six separate animal containers. The animals were euthanized and necropsied within 4 hours of arrival, and blood was collected for determination of complete blood counts, a serum chemical chemistry screen and a serology screen. All organs were examined grossly and nasal passages, salivary glands, trachea, liver and kidneys were processed for histolopathological examination.

Environmental Conditions:
-Temperature: 71-78 °F
-Humidity: 33-59%
-Three excursions outside the temperature and humidity limits were neither large nor long-standing, and were not considered to have affected the test animals adversely.
-Photoperiod: 12:12 light:dark
-Air exchange: The room that the animals were housed in was equipped with a laminar flow air system.

In-Life Study Dates:
-Study Initiation Date: August 10, 1984
-Experimental Start Date: September 5, 1984
-Experimental Completion Date: March 13, 1985


Route of administration:
oral: feed
Vehicle:
other: Purina Laboratory Rodent Chow 5002 (certified)
Details on oral exposure:
Rats (20 rats/sex/group) were exposed per os to di (2-ethylhexyl) terephthalate at dose concentrations of 0.1, 0.5, or 1.0% in a diet of Purina Laboratory Rodent Chow 5002 (certified) for 90 days. Control animals (20 rats/sex) were provided the standard rat chow without any added di (2-ethylhexyl) terephthalate.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of di (2-ethylhexyl) terephthalate in the diet:
The concentration of di (2-ethylhexyl) terephthalate in the test diets was determined by extraction with acetonitrile and subsequent analysis by HPLC.

Homogeneity of di (2-ethylhexyl) terephthalate concentrations in the diet:
All diets were tested for homogeneity by analyzing samples of the diet taken from the top, middle and bottom of the mixing container. In addition, following termination of use of each batch of diet, a small amount of the remaining mixture was re-analyzed to confirm stability. With a single exception, the diets proved to be homogeneous, with no more than 3-4% variation between the measured concentrations from the top to the bottom of a batch. The single non-homogeneous diet was remixed before it was used on study and reanalysis confirmed the homogeneity of the remixed diet.

Stability of di (2-ethylhexyl) terephthalate in the diet:
-Test diets containing either 0.1 or 1.0% di (2-ethylhexyl) terephthalate in the feed were prepared prior to study initiation and were analyzed once a week for 6 weeks. The analyses of these diets indicated that little degradation of di (2-ethylhexyl) terephthalate occurred with time, with all samples yielding equal to or greater than 90% of the target dose. Di (2-ethylhexyl) terephthalate was considered to be stable for six weeks when mixed with ground laboratory chow. The mean analyzed concentration of the 1.0, 0.5 and 0.1% diets was 0.983, 0.490, and 0.096%, respectively, at the time of mixing. Analyses of the same diets after use on the study revealed the concentrations to be 0.937, 0.460, and 0.091%. In agreement with the above analysis, the comparison of final versus initial concentration revealed a loss of only 8% or less in all diets, as final dietary concentrations of di (2-ethylhexyl) terephthalate, when measured in the experimental diets six weeks after mixing, averaged 92.3% of the original target dose.
-Dose level selection:
The high dose was set at 1% in order to provide a significant exposure to the test substance without markedly changing the nutritive characteristics of the diet, whereas the two other dose levels were chosen to represent 1/2 and 1/10 of the high dose. Previous experience at the testing facility with palatable compounds mixed into diets at a concentration of 1.0% resulted in a dose level of nearly 1000 mg/kg bw/day when offered to a growing animal.
Duration of treatment / exposure:
Approximately 90 days (ad libitum)
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0.1% (54 mg/kg bw/day male and 61 mg/kg bw/day female)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.5% (277 mg/kg bw/day male and 309 mg/kg bw/day female)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1.0% (561 mg/kg bw/day male and 617 mg/kg bw/day female)
Basis:
nominal in diet
No. of animals per sex per dose:
20 per sex per dose
Details on study design:
Rats (20 rats/sex/group) were exposed per os to di (2-ethylhexyl) terephthalate at dose concentrations of 0.1, 0.5, and 1.0% in the diet for approximately 90 days. Control animals (20 rats/sex) were provided standard rat chow without the test substance. The following examinations/ measurements were conducted during the course of the study: clinical observations, body weights, food consumption, clinical chemistry, hematology, urinalysis, and hepatic peroxisome proliferation. At the end of the study, all animals were subjected to a gross necropsy, select organ weights were measured, and histopathology was performed.
Positive control:
For the peroxisome study, five male rats were randomly assigned to receive a positive control substance (2-ethylhexanol; known to cause liver enlargement and hepatic peroxisome proliferation) at a dose level of 1500 mg/kg bw/day by oral gavage. Due to excessive toxicity after three doses, the dose level was reduced to 1000 mg/kg bw/day starting on day 4. Dosing continued for a total of 3 consecutive weeks.
Observations and examinations performed and frequency:
Examinations: Clinical examinations were conducted on Days 0, 3, 7, and once each week thereafter. Cage side observations were conducted each weekday afternoon and on mornings the examinations were not conducted. Cage side observation included, but was not limited to, examination of the hair, skin, eyes, motor activity, feces and urine.

Body Weights: Body weights were measured prior to study start, on Days 0, 3, 7, and weekly thereafter.

Feed Consumption: Feed consumption was determined on Days 3, 7 and twice weekly thereafter, except during Week 12 when it was determined only once.

Ophthalmic examinations: Ophthalmic examinations were performed on all animals prior to study start and at study termination.

Urinalysis: Ten animals were randomly selected for urine zinc analysis during Weeks 12 and 13. Selected animals were transferred to Nalgene metabolism cages for 24 hours for urine collection on two consecutive days. Urine volumes were measured and quantitation of zinc concentrations and calculation of total zinc excreted were determined.

Clinical Chemistry: Blood was collected from the posterior vena cava while the animals were under CO2 anesthesia at the time of necropsy. The following parameters were examined on blood from 10 animals/sex/dose level: Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, urea nitrogen, glucose, creatinine, sorbitol dehydrogenase, gamma glutamyl transpeptidase, triglycerides, cholesterol, total protein, albumin, albumin/globulin ratio, and total bilirubin.

Hematology: Blood was collected from the posterior vena cava at the time of necropsy (see above), and the following parameters were examined on all 20 animals/sex/dose level: red blood cell count, hemoglobin concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, prothrombin time, Heinz body count, white blood cell count, differential white blood cell count, nucleated red blood cell count, and red and white blood cell morphology.

Sacrifice and pathology:
Study Termination: Animals were necropsied on Days 91-94. All animals were fasted overnight prior to necropsy. On the day of necropsy, the animals were anesthetized with CO2 and blood was collected from the posterior vena cava for hematology and clinical chemistry analysis. The animals were euthanized by exsanguination and subjected to a complete necropsy.

Organ Weights: Liver, kidneys, heart, adrenal glands, spleen, testes, ovaries, and brain. Paired organs were weighed together.

Tissues Collected and fixed in 10% buffered formalin: Trachea, lungs, thymus, heart, aorta, tongue, salivary glands, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, pancreas, liver, kidneys, urinary bladder, adrenal glands, pituitary gland, thyroid glands, parathyroid glands, spleen, mesenteric lymph nodes, femoral bone marrow, quadriceps femoris muscle, skin, rib, femur, brain, cervical spinal cord, sciatic nerve, testes, epididymides, male accessory sex glands, male mammary gland, ovaries, uterus, vagina, fallopian tubes, female mammary glands and gross lesions. The eyes were collected and fixed in Zenker's (Russell's) fixative.

Histopathology: All collected tissues from the high-dose and control groups were examined microscopically. Target organs and gross lesions in other dose groups were also examined.
Other examinations:
Peroxisome Analysis: Five male rats from the treated and control groups were randomly selected for the peroxisome assay. Additionally, a group of five male rats treated with 1000 - 1500 mg 2-ethylhexanol/kg by gavage 5 days/week for the last 3 weeks of the study served as positive controls. The livers from these animals were removed at necropsy and fixed in 5% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4. Samples were immersed in a peroxidase reaction medium containing 3,3’-diaminobenzidine. Following staining, the samples were rinsed in buffer and post-fixed in Dalton’s chrome-osmium solution, dehydrated, and embedded in Epon 812 epoxy resin. Samples were thin-sectioned using a microtome and examined using a Hitachi H600 electron microscope. One randomly chosen field from each of five blocks per rat was photographed, and morphometric analysis was accomplished using an Elographics digitizer attached to a PDP 11/44 computer. A computer program was used to calculate peroxisome area, peroxisome cell fraction, and the number of peroxisomes per 100 µm2 of hepatocyte cytoplasm.
Statistics:
All numerical data were evaluated using the following computerized statistical models: one-way analysis of variance (ANOVA), Bartlett's test, and Duncan's multiple range test. Additional procedures used in the peroxisome assay included the F-test and the Student's t-test.
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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
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: Clinical abnormalities observed during the study were limited to transitory enlargement of the salivary glands, malocclusion of the incisors, and porphyrin nasal discharges. None of these abnormalities were considered treatment-related.

Body Weight Gains: Mean body weight gains were comparable among groups throughout the study.

Food Consumption: Mean feed consumption values were comparable among groups during the course of the study. Indications of slight decreases in food consumption were observed at two points for females during the study, but these were considered spurious and unrelated to the test material.

Male rats consumed an average of 26.85 grams of feed/day throughout the study, and females consumed an average of 19.13 grams/day. Initial daily consumption of the test material for animals consuming the 1.0% diet was 800 mg/kg/day in males and 750 mg/kg/day in females. The overall mean consumption over the study was 561 and 617 mg/kg/day in males and females, respectively, consuming the 1.0% diet. Effective daily doses were 277 and 309 mg/kg in the 0.5% males and females, and 54 and 61 mg/kg in the 0.1% males and females, respectively.

Ophthalmoscopic examination: During the acclimation period, four animals were found to have abnormalities of the eye and were eliminated from the animal pool. The remaining animals were in good general health. None had ophthalmologic abnormalities, and all were released to the study. The animals randomly assigned to the study were examined again for ophthalmologic irregularities during week 13, and none were found to have any abnormalities of the eye at the second examination.

Hematology: Mean hemoglobin, hematocrit, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV)values were significantly lower for male rats from the 1.0% dose group, though absolute reductions averaged only 4-5%. Mean MCH values were also lower for male rats from the 0.5% (2% lower) dose group. For female rats, mean MCV and MCH values were significantly lower for the 1.0 and 0.5% dose groups; reductions averaged 3%. Hemoglobin concentration was slightly and significantly decreased at 0.1% in the diet but this finding was considered spurious since the difference was not present in animals consuming 0.5% di (2-ethylhexyl) terephthalate in the diet.
Examination of red cell morphology in males revealed a number of variations in erythrocyte appearance in all groups which included: microcytosis, anisocytosis, poikilocytosis, and spherocytosis. Single animals had incidences of minimal macrocytosis (0.1% group) and minimal presence of Howell-Jolly bodies (0.5% group). Similar variations were observed in the females, though not as many animals were identified as having each abnormality. The observations made on the morphological characteristics of the red blood cells did not fit a recognizable pattern and were determined to be unrelated to di (2-ethylhexyl) terephthalate exposure and cell morphology observations were not corroborated by calculated numerical changes in hematocrit, hemoglobin concentration, or red cell indices.
No biologically significant differences were seen among males between treated and control animals in white blood cell count, differential white blood cell count, platelet count or prothrombin time. Statistically significant differences were observed in the percentage of polymorphonuclear leukocytes, lymphocytes, and eosinophils, when control animals were compared to animals fed diets containing 0.1 or 0.5% di (2-ethylhexyl) terephthalate. However, the differences were not dose related, as they were not observed in hematology data obtained from animals fed the 1.0% diets. No biologically or statistically significant differences in any of the observed parameters were observed in the females.
Since these changes in hematology were minimal in severity (less than 5%), not dose-dependent, and not accompanied by other abnormalities indicative of anemia, they were not considered to be biologically significant.

Clinical Chemistry: Changes in clinical chemistry parameters were limited to lower mean glucose values for female rats from the 0.1% dose group. However, since this change was not seen in any of the other dose groups, it was considered to be incidental. All other clinical chemistry values were comparable among groups.

Urinalysis: There were no treatment-related differences in urinary zinc concentrations.

Gross Pathology: No test substance-related abnormalities were observed during gross examination of the animals.

Organ Weights: In the males, absolute liver weight was increased by 9% and liver weights relative to body weights were increased 11% in animals consuming 1.0% di (2-ethylhexyl) terephthalate in the diet when compared to controls. These changes were not statistically significant. In contrast to the findings regarding absolute weight, the increase in relative liver weight was statistically significant. In females, the liver weights were similar to those observed in the males; the absolute liver weight was increased by 7% and the relative liver weight was increased by 9% in animals provided the 1.0% di (2-ethylhexyl) terephthalate diet. Similar to what was observed in males, the elevation in relative weights in females was statistically significant at the 1% level, but the absolute weight was not. No other mean absolute or relative (to body weight) organ weights were significantly altered in either sex. When organ weights were expressed relative to brain weights, no changes were present in either sex, though a trend was observed toward increasing relative liver to brain weights in both sexes at 1.0% in the diet. The differences did not reach statistical significance, but liver to brain weight ratios were increased 9 and 10% in the males and females, respectively, when compared to controls.

Histopathology: Histopathological examinations of organs from the control and high-dose groups as well as gross lesions from other groups did not reveal any treatment-related effects. The abnormalities observed in tissues from the animals were limited to lesions commonly observed in animals of this strain in the testing laboratory.

Peroxisome Assay: Based on the results of the peroxisome assay, there was no indication of peroxisome induction in animals from the 1.0% dose group. In contrast, the positive control caused a 28% increase in the liver peroxisome fraction and a 33% increase in peroxisome density.
Dose descriptor:
NOEL
Effect level:
277 other: mg/kg/day
Sex:
male
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
309 other: mg/kg/day
Sex:
female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

Quality control animals:

The profile of results on the quality control animals was similar to that routinely obtained from the vendor and correlated well with historical data obtained within the testing facility.

Conclusions:
When di (2-ethylhexyl) terephthalate was administered to rats via the diet at concentrations of 0, 0.1, 0.5, and 1% for 90 days, the NOEL for systemic toxicity was determined to be 0.5% (equivalent to 277 and 309 mg/kg bw/day for males and females, respectively) based on minor effects on red blood cell formation, and enlargement of the liver in both sexes at a dose concentration of 1.0%.

There were no deaths, no functional changes in any organ system, and no significant adverse effects on clinical chemistry parameters, hematology or urinalysis during the course of the study. Although there was a statistically significant increase in relative liver weight to body weight ratios for both sexes at the 1% dose level, there was no corresponding organ damage seen at gross or microscopic examination, no evidence of liver dysfunction, and no effects on clinical chemistry parameters that would be suggestive of liver damage. Based on an absence of significant effects and clear NOEL values of 277 mg/kg bw/day and 309 mg/kg bw/day for males and females, respectively, following exposure in the diet for 90 days, di (2-ethylhexyl) terephthalate is not classified for “Specific Target Organ Toxicity – Repeated Exposure” according to GHS.

Executive summary:

In a subchronic dietary toxicity study, di (2-ethylhexyl) terephthalate was administered to 20 rats/sex/group at target concentrations of 0, 0.1, 0.5, and 1.0% continuously for 90 days. All animals survived and there were no treatment-related clinical signs. Toxicity related to the administration of di (2-ethylhexyl) terephthalate was limited to minor effects on red blood cell formation, and enlargement of the liver in both sexes at a dose concentration of 1.0%. There were no corresponding functional changes in the liver, no gross or microscopic liver changes, and no adverse effects on any clinical chemistry parameters that would indicate liver damage. All other findings in the study occurred in a non dose-dependent manner, were spurious in nature, or were biologically irrelevant and were not considered related to di (2-ethylhexyl) terephthalate consumption. Under the conditions of this study, the NOEL in male and female rats exposed via the diet to di (2-ethylhexyl) terephthalate was 277 and 309 mg/kg bw/day in males and females, respectively.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
277 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
key study

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
10 days
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study conducted prior to introduction of Good Laboratory Practices; data from a summary report; limited number and no information on sex of animals. 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 test material. 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
Principles of method if other than guideline:
Undiluted di (2-ethylhexyl) terephthalate was applied 9 times over 11 days to the clipped skin of 5 guinea pigs. The 0.5 mL dose applied equates to 813 to 1144 mg/kg bw/day. Animals were observed for clincal abnormalities and body weight changes. No necropsy was performed at study termination.
GLP compliance:
no
Remarks:
Study conducted prior to GLPs
Limit test:
yes
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
not specified
Details on test animals or test system and environmental conditions:
Test animals:
-Sex: no data
-Weight at study initiation: 430 - 605 g
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
-Test Substance Application: The test substance was applied to the clipped skin of animals once a day for 9 applications over an 11 day period. The material was dropped onto the backs of the animals and spread gently over the back with a glass rod.

-Occlusion: None

-Total Volume Applied: 0.5 mL/day for a total amount equal to 4.5 mL. Based on initial body weights, the dose equates to 813 to 1144 mg/kg bw/day.

-Removal of Test Substance: It is not specified if the site of application was washed (with water or a solvent) or wiped at the end of each exposure period.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Once daily
Frequency of treatment:
9 applications over an 11 day period
Remarks:
Doses / Concentrations:
Based on initial body weights, the dose equates to 813 to 1144 mg/kg bw/day.
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 (sex not reported)
Control animals:
no
Observations and examinations performed and frequency:
-Examinations: Animals were observed for clinical abnormalities.

-Body Weights: Body weights were collected on Day 0 and at study termination.

-Feed Consumption: Feeders were not weighed.
Sacrifice and pathology:
Animals were euthanized at the end of the study; gross necropsies were not performed.
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
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:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
-NOEL: Not established.

-Mortality: No mortality was observed during the study.

-Clinical abnormalities: The first application produced moderate erythema in one animal and severe erythema in the other four. Slight edema was observed for all animals but this disappeared by study termination. The reaction did not change over the course of two weeks. Necrosis and eschar were not observed during the study.

-Body Weight: All animals gained weight during the study.
Critical effects observed:
not specified
Conclusions:
In a subacute dermal toxicity study, 5 guinea pigs were exposed to 0.5 mL undiluted di (2-ethylhexyl) terephthalate (equating to 813 to 1144 mg/kg bw/day) 9 times over 11 days. The material was dropped onto the backs of the guinea pigs and spread gently over the back skin with a glass rod. No signs of skin absorption or systemic toxicity were evident during the study. Under the conditions of this study, there was no exacerbation of the irritant response with repeated applications of di (2-ethylhexyl) terephthalate. Based on the results of this study, di (2-ethylhexyl) terephthalate is not classified for “Specific Target Organ Toxicity – Repeated Exposure” according to GHS.
Executive summary:

In a subacute dermal toxicity study, 5 guinea pigs were exposed to 0.5 mL undiluted di (2-ethylhexyl) terephthalate (equating to 813 to 1144 mg/kg bw/day) 9 times over 11 days. Under the conditions of this study, no deaths occurred and no signs of skin absorption or systemic toxicity were evident during the study. At the application sites, signs of irritation were limited to moderate to severe erythema and slight edema. During the course of two weeks the erythema did not diminish in severity but the edema disappeared. 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 is not acutely toxic following repeated dermal application but may cause moderate irritation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
813 mg/kg bw/day
Study duration:
subacute
Species:
guinea pig
Quality of whole database:
2 (reliable with restrictions)

Additional information

The potential for di (2-ethylhexyl) terephthalate to cause target organ toxicity following repeated exposure is well understood. Two key guideline and four lesser non-guideline studies were available for review. The first key study is considered to be a 90-day feeding study in rats conducted according to GLPs and EPA guideline 799.9310. In this repeat-exposure study in which male and female rats were exposed to 0.1, 0.5 or 1.0% of di (2-ethylhexyl) terephthalate in the diet for 90 days, there were no deaths or functional changes in any organ system and no significant adverse effects on food consumption, ophthalmic examination, clinical chemistry parameters, urinalysis, or gross/microscopic pathology. Adverse effects were limited to minor effects in hematology parameters and increases in relative liver weights in both sexes. The latter occurred in the absence of liver dysfunction, gross/microscopic changes, or changes in clinical chemistry parameters that would be suggestive of target organ effects. There was also no indication of an increase in peroxisome proliferation at the highest concentration tested (equivalent to 561 and 617 mg/kg bw/day for male and female rats, respectively). The NOEL for systemic effects was considered to be 277 mg/kg bw/day and 309 mg/kg bw/day for males and females in this study. The second key study is a 2-year carcinogenicity study conducted according to EPA OPPTS Guideline 870.4200 in which male and female rats were exposed to 1500, 6000 or 12000 ppm in the diet for a lifetime. The highest dose level was equivalent of 666 and 901 mg/kg bw/day in males and females, respectively. Like the 13-week study, increases in relative liver weights were observed in high-dose groups of both sexes but this again occurred in the absence of gross/microscopic changes or changes in clinical chemistry parameters. The observed changes were considered an adaptive change rather than an indication of target organ toxicity.

  

In addition, several shorter non-guideline studies conducted by a variety of routes were considered in the overall evaluation. Because the structural analog di-(ethylhexyl) phthalate (DEHP) caused significant peroxisome proliferation in rats following oral administration, groups of male and female rats were exposed to di (2-ethylhexyl) terephthalate in the diet at concentrations of 0.1, 0.5, 1.0, 1.2 and 2.5% for comparison. The latter two concentration levels of DEHP caused moderate to marked peroxisome proliferation in rats exposed via the diet. Following administration of di (2-ethylhexyl) terephthalate ad libitum in the diet at concentration levels up to 2.5% for 21 days, effects on lipid metabolism and slight peroxisome proliferation were observed only in the 2.5% exposure group (equivalent to 2104 and 1900 mg/kg bw/day for male and female rats, respectively). At this dose level, there was a significant decrease in food consumption and body weight gain and a variety of adverse clinical signs. Since fasting alone has been implicated in the formation of hepatic peroxisomes and altered lipid metabolism, it is likely that effects observed in this study were related to feed restriction rather than exposure to di (2-ethylhexyl) terephthalate alone. No treatment-related changes were observed in the kidneys or testes. Based on the study conditions, the NOEL for 21-day exposure via the diet was considered to be 0.5% which corresponded to 505 and 487 mg/kg bw/day for male and female rats, respectively. Minimal effects were observed at 1% (equivalent to 1037 mg/kg bw/day for males and 1052 mg/kg bw/day for females). In a third supporting oral study, there were no adverse effects on survival, clinical observations, body weight, hematology, clinical chemistries, or gross/microscopic examinations in male rats receiving up to 1% di (2-ethylhexyl) terephthalate in the diet for 10 days (equivalent to 885 mg/kg bw/day).

  

In a subacute dermal toxicity study, no deaths, signs of skin absorption or systemic toxicity were evident when guinea pigs were exposed to 0.5 mL of undiluted di (2-ethylhexyl) terephthalate (equating to 813 - 1144 mg/kg bw/day) for 9 exposures over an 11 day period. There were no gross or microscopic examinations conducted in this study. In a subacute inhalation study in which male rats were exposed to a mean concentration of 0.0718 mg/L (highest concentration that could be generated by heating the test material to 95°C) for 6 hours/day, 5 days/week for 2 weeks, no deaths or signs of toxicity were evident during the study.  Hematology and clinical chemistry parameters were within the normal ranges for the control and test group and there were no significant treatment-related gross or microscopic effects observed at necropsy. 

  

Justification for classification or non-classification

No significant target organ effects were observed in male or female rats following ad libitum exposure to up to 1% in the diet for 90 days (resulting in overall mean consumption over the study of 561 and 617 mg/kg bw/day in males and females, respectively). Toxicity related to test substance administration was limited to minor effects on red blood cell formation and enlargement of the liver with no corresponding adverse effect on liver function, clinical chemistries or gross/microscopic pathology. The overall NOEL for the 90-day feeding study was 0.5% in the diet (equivalent to 277 and 309 mg/kg bw/day for males and females, respectively). There was no evidence of peroxisome proliferation in the 90-day study at the highest concentration tested. There were also no significant target organ effects in a 2-year feeding study in which groups of male and female rats were provided ad libitum access to a diet containing up to 12000 ppm of di (2-ethylhexyl) terephthalate. Several lesser oral studies of shorter duration support results observed in the 90-day feeding study. In addition, no signs of absorption or systemic toxicity were observed following administration of 0.5 mL of undiluted di (2-ethylhexyl) terephthalate to the backs of guinea pigs for a total of 9 exposures over an 11 day period (equivalent to 813-1144 mg/kg bw/day). This dose level did cause moderate to strong erythema. There were also no deaths, no adverse clinical signs, no effects on hematology or clinical chemistry, or gross/microscopic changes in rats exposed 6 hours/day, 5 days/week for 2 weeks to the highest vapor concentration that could be generated by heating di (2-ethylhexyl) terephthalate to 95°C. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for target organ toxicity following repeated exposure. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate would not be classified for “Specific Target Organ Toxicity – Repeated Exposure” 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.