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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status unknown, non-guideline study, published in peer reviewed literature, no restrictions, fully adequate for assessment
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Inhalation developmental neurotoxicity study of ethylbenzene in Crl-CD rats
Author:
Faber WD, Roberts LSG, Stump DG, Beck M, Kirkpatrick D, Regan KS, Tort M, Moran E and Banton M
Year:
2007
Bibliographic source:
Birth Defects Res (Part B) 80:34-48

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: EPA OPPTS 870.3800 (Reproduction and Fertility Effects)
Deviations:
yes
Remarks:
inclusion of developmental neurotoxicity assessment
Principles of method if other than guideline:
2-generation reproduction study with evaluation of F2 offspring for nervous system functional and morphological end points
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- CAS number: 100-41-4
- Source: The Dow Chemical (Midland, MI) via Ashland Chemical (Morrisville, PA, USA)
- Storage: under refrigeration
- Analytical purity: at least 99.9%

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)IGS BR
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories (Raleigh, NC, USA) on 8 April 2003
Details on acclimation, husbandry and welfare published in Faber et al., 2006

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air
Details on exposure:
Not described in this publication but in earlier publication by Faber, 2006.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Exposure chambers, gas chromatography with flame ionization detection. Analysed concentrations were very close to nominal.
Dosing solutions, gas chromatography with mass spectroscopy.
Details on mating procedure:
1 male:1 female for 14 days or until confirmation of mating observed
Duration of treatment / exposure:
Inhalation: 6 hours daily, 7 days per week. F0 and F1 animals exposed for at least 70 consecutive days prior to mating. Males continued on the same regime whilst on study. The females were similarly exposed throughout mating and gestation, through to day GD 20; exposure recommenced on day 5 of lactation (LD5) and continued through to weaning (LD21).
Oral gavage: females only days 1-4 of lactation. Ethylbenzene administered in corn oil at dose levels of 0, 26, 90, and 342 mg/kg/day (dose levels selected to result in similar internal maternal exposure based on PBPK modelling). Each dose was divided into 3 equal amounts and administered approximately two hours apart.
Frequency of treatment:
Daily
Duration of test:
Approximately 42 weeks
No. of animals per sex per dose:
30 F0, 25 F1
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Parental animals observed twice daily for mortality and clinical signs.
FOB: F1 dams GD6 and 12 and on LD 10 and 21
Statistics:
Analyses were conducted using two-tailed tests for a minimum significance level of 5%, comparing each test group to the control group. The litter was used as the unit of analysis where appropriate as was analysis by gender.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Remarks:
ethyl benzene
Effect level:
>= 500 ppm
Basis for effect level:
other: other:

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEC
Remarks:
Ethylbenzene
Effect level:
>= 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEC for physical and neurobehavioural development of the F2 offspring from a 2-generation study was 500 ppm ethylbenzene (equivalent to 2171 mg/m3).
Executive summary:

Male and female Crl:CD(SD)IGS BR rats were exposed by inhalation to 0, 25, 100 or 500 ppm ethylbenzene for 6 hr/day throughout a 2-generation study except for females between lactation days 1 and 4 when the dose was administered in corn oil by oral gavage at dose levels of 26, 90 or 342 mg/kg/day (to provide similar maternal blood (AUC) as provided by inhalation). The physical and neurobehavioural development of the F2-generation was evaluated using a number of developmental landmarks, a functional observational battery, a motor activity assessment, an acoustic startle response and a learning and memory task. Evaluations of whole-brain measurements and brain morphometric and histological assessments were also included.

Parental exposure to ethylbenzene at concentrations up to and including 500 ppm did not adversely affect the survival of the F2 offspring, their clinical condition or body weight or their acquisition of several developmental landmarks. No treatment-related alterations were detected in the FOB tests, the motor activity counts, acoustic startle endpoints or the performance in the Biel water maze. Furthermore, no exposure-related differences were evident from the neuropathology assessments. The NOAEC for physical and neurobehavioural development was 500 ppm ethylbenzene.