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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published read-across study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
DEHT was obtained from Eastman Chemical Company (98.4-98.9% purity)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, MA, USA
- Age at study initiation: 6 weeks
- Weight at study initiation: 250 +/- 50 g (M), 200 +/- 50 g (F)
- Housing: Groups of 5 (single sex)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 35-59
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Groups of rats were exposed in the diet to DEHT at concentrations of 0 (plain diet, control), 0.1, 0.5 or 1.0% for 90 days.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC following exctraction of dietary samples with acetonitrile, at weekly intervals.
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily / continuous
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.1, 0.5, 1.0
Basis:
nominal in diet
No. of animals per sex per dose:
20/sex/dose
Control animals:
yes, plain diet
Details on study design:
Groups of 20 rats/sex were exposed in the diet to DEHT at concentrations of 0 (plain diet, control), 0.1, 0.5 or 1.0% for 90 days.
Positive control:
An additional group was administered the known peroxisome proliferator 2-ethyhexanol.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Day 0, 3, 7 and then weekly

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 3, 7 and then weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: terminal
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 20

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: terminal
- Animals fasted: No data
- How many animals: 10

URINALYSIS: Yes
- Time schedule for collection of urine: Week 12-13
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
All rats were subject to gross autopsy; weights of the lver, kidneys, heart, adrenals, spleen, testes, overoes and brain were recorded. Histopathoogy was performed on tissues from control and high dose level animals.
Other examinations:
Five male rats from each group were examined for liver peroxisome proliferation uisng immunohistochemistry
Statistics:
Numerical data were evaluated by one-way ANOVA, Bartlett's and Duncan's test.

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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
: effects on red blood cell parameters at 1.0%; minimal effects at 0.5%
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
Description (incidence and severity):
Increased relative liver weight at 1.0%
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: no effects were observed

BODY WEIGHT AND WEIGHT GAIN: unaffected by treatment

FOOD CONSUMPTION AND COMPOUND INTAKE: food consumption was unaffected by treatment. Mean calculated intakes of DEHT were 54/61 mg/kg bw/d, 277/309 mg/kg bw/d and 561-617 mg/kg bw/d at 0.1, 0.5 and 1.0% respectively.

HAEMATOLOGY: Red blood cell parameters (haemoglobin concentration, haematocrit, MCV and MCH were reduced in males at 1.0%. MCH was also reduced in males at 0.5%. Reduced MCV and MCH values were seen in females at 0.5 and 1.0%.

CLINICAL CHEMISTRY: no effects of treatment

URINALYSIS: no effects of treatment

ORGAN WEIGHTS: mean relative liver weight was increased in both sexes at 1.0%

GROSS PATHOLOGY: no findings

HISTOPATHOLOGY: NON-NEOPLASTIC: no findings

Effect levels

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Dose descriptor:
NOAEL
Effect level:
277 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Effects on red blood cell parameters and increased relative liver weight at 1.0% (561 mg/kg bw/d)
Dose descriptor:
NOAEL
Effect level:
309 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Effects on red blood cell parameters and increased relative liver weight at 1.0% (617 mg/kg bw/d)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Effects on haematological parameters at 0.5% (reduced MCV in males; reduced MCV and MCH in females) are not considered to be of toxicological significance in the absence of effects on erythrocyte count or haematocrit. There was no evidence of hepatic peroxisome proliferation in rats treatde with DEHT, in contrast to the positive control group.

Applicant's summary and conclusion

Conclusions:
Effects of treatment with DEHT were limited to reduced erythrocyte parameters at 0.5% and 1.0% and increased relative liver wieght at 1.0%. Effects on haematological parameters at 0.5% (reduced MCV in males; reduced MCV and MCH in females) are not considered to be of toxicological significance in the absence of effects on erythrocyte count or haematocrit. A NOAEL of 0.5% is therefore determined for this study, equivalent to mean achieved intakes of 277 and 309 mg/kg bw/d in males and females, respectively.
Executive summary:

Di(2-ethylhexyl) terephthalate (DEHT), the 2-ethylhexyl diester of terephthalic acid was administered in the diet to groups of 20 male and female Sprague-Dawley rats for 90 days at concentrations of 0.0, 0.1, 0.5 or 1.0%. No major organ or systemic toxicity was observed in any group. Changes that were observed included slight effects on some haematology parameters including haemoglobin concentration, haematocrit, mean corpuscular volume and mean corpuscular haemoglobin and slight increases in relative liver weights (11.2% and 8.9% in males and females respectively) at 1.0%. Marginal changes some erythrocyte parameters were also observed at 0.5%. In a morphometric study of liver sections, DEHT was found not to induce hepatic peroxisomes. A NOAEL of 0.5% (5000 ppm, equivalent to mean achieved intakes of 277 and 309 mg/kg bw/d in males and females, respectively.