Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2000-2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study conducted according to internationally recognised test methods

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
TEHTM Study for effects on embryo-fetal and pre- and post-natal development in CD rat by oral gavage administration
Author:
Anon.
Year:
2002
Bibliographic source:
EPA TSCATS low detail report
Reference Type:
publication
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tri-(2-ethylhexyl)trimellitate (TEHTM)
- Analytical purity: 98.93%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
No details available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: No details available
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
No details available
Duration of treatment / exposure:
Gestation days 6-19 (prenatal development)
Gestation day 6 - post-partum day 20 (post-natal development)
Frequency of treatment:
Daily, except day of parturition for animals allowed to litter
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 500, 1050 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
35 females/group - 20 for pre-natal development; 15 for post-natal development
Control animals:
yes, concurrent vehicle
Details on study design:
No details available

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

POST-MORTEM EXAMINATIONS: No data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: No data
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
Statistics:
ANOVA followed by William’s test, or Kruskal-WaIlis/Hollander & Wolfe followed by Shirley’s test, Steel’s test, Cochran-Armitage, Fisher’s exact test.
Indices:
No data
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No significant effects on bodyweight or gravid uterus weight at any dose level, either during gestation or lactation. No inter-group differences regarding the number of implantations, post-implantation loss, gestation length and index, or (live) litter size.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 050 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 050 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant differences in foetal body weights. No significant variations or malformations observed in gross external appearance, viscera, skeletal system, or anogenital distance of pups.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Post-natal development examinations did not reveal any significant differences relative to controls for survival of offspring, sex ratio, bodyweight or bodyweight gain, auditory startle and pupil closure responses, age at vaginal opening or preputial separation.

At necropsy, there were no effects attributable to treatment in either females (6 weeks of age) or males (15 weeks of age). Assessment included morphology of the male and female reproductive tract organs, weight of the male reproductive organs or microscopic pathology of the testis.

 

There was a slight but statistically significant (P<0.05) increase in the number of male animals with retained areolar regions on evaluation at post-natal Day 13 at 1050 mg/kg/day. Affected animals had only one or two more sites than those in the control group. The areolae present at post-natal Day 13 were no longer present on re-examination on post-natal Day 18. In the absence of any other supporting data, this finding was regarded as being of questionable toxicological significance.

There was a higher incidence of displaced testes in foetuses from the group treated at 1050 mg/kg/day when compared with controls. However, the incidence was within the range of recent historical control data of the test facility for this endpoint. No displaced testes were noted in any of the foetuses undergoing less rigorous examination prior to preparation for skeletal examination. There was no difference in the incidence of non-scrotal testes between males of treatment and control groups at 15 weeks of age.

The incidence of renal cavitation was higher controls in foetuses that were macroscopically assessed prior to skeletal examination. Again, this finding was within the range of recent historical control values, and was not found during examination of foetuses by the more rigorous serial sectioning technique.

The incidence of effects in the testes and kidneys appear to be related to the low incidence of these findings in the concurrent control group compared to the range of historical control values. The observed incidences of these findings in treated groups were within the range of historical controls from recent studies at the test facility and they were not supported by complimentary observations made in foetuses or offspring. They were therefore considered not to be related to treatment.

 

Applicant's summary and conclusion

Conclusions:
A developmental toxicity study in the rat, extended to permit an assessment of post-natal development, found no treatment-related effects indicative of maternal toxicity. No effects on offspring body weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or female offspring that were attributed to treatment.

NOEL maternal toxicity: 1050 mg/kg/day
NOEL pre-natal developmental toxicity: 1050 mg/kg/day
NOEL post-natal evaluation of offspring: 500 mg/kg/day; LOAEL: 1050 mg/kg/day
Executive summary:

A developmental toxicity study in the rat, extended to permit an assessment of post-natal development, found no treatment-related effects indicative of maternal toxicity. No effects on offspring body weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or female offspring that were attributed to treatment.

NOEL maternal toxicity: 1050 mg/kg/day

NOEL pre-natal developmental toxicity: 1050 mg/kg/day

NOEL post-natal evaluation of offspring: 500 mg/kg/day; LOAEL: 1050 mg/kg/day