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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from Publication

Data source

Reference
Reference Type:
publication
Title:
Route-to-route extrapolation of 1,2-dichloroethane studies from the oral route to inhalation using physiologically based pharmacokinetic models
Author:
Lisa M. Sweeney*, Michael L. Gargas
Year:
2016
Bibliographic source:
Regulatory Toxicology and Pharmacology 81 (2016) 468-479

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Principles of method if other than guideline:
Extended one generation toxicity (EOGRT) study of 1,2-dichloroethane in Rats
GLP compliance:
not specified
Limit test:
no
Justification for study design:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1,2-dichloroethane
- Molecular formula (if other than submission substance): C2H4Cl2
- Molecular weight (if other than submission substance): 98.9596 g/mole
- Substance type: Organic
Specific details on test material used for the study:
- Name of test material (as cited in study report): 1,2-dichloroethane
- Molecular formula (if other than submission substance): C2H4Cl2
- Molecular weight (if other than submission substance): 98.9596 g/mole
- Substance type: Organic

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD
Sex:
male/female

Administration / exposure

Route of administration:
oral: drinking water
Type of inhalation exposure (if applicable):
not specified
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
not specified
Frequency of treatment:
Daily
Details on study schedule:
not specified
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Total: 216
0 mg/kg/day: 27 male, 27 female
50 mg/kg/day: 27 male, 27 female
150 mg/kg/day: 27 male, 27 female
300 mg/kg/day: 27 male, 27 female
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
not specified

Examinations

Parental animals: Observations and examinations:
Body weight and body weight gain were observed
Estrous cyclicity (parental animals):
Estrous cyclicity in P females was evaluated.
Sperm parameters (parental animals):
Sperm count, motility, and morphology were determined for all adult males were examiined.
Litter observations:
Reproductive/developmental effects (Cohort 1), neurodevelopmental effects (Cohort 2), and developmental immune effects (Cohort 3) were examined.
Postmortem examinations (parental animals):
Oragn weight, gross pathology and histopathology were examined.
Postmortem examinations (offspring):
not specified
Statistics:
not specified
Reproductive indices:
Fertility, gestation, vaginal opening and preputial separation were observed.
Offspring viability indices:
not specified

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Decrease in body weight and body weight gain were observed in treated rats as compared to control.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
As EDC in drinking water to have poor palatability; drinking water consumption was generally decreased, relative to Controls, in a dose-related manner.
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Change in relative liver weight were observed in F0 female rats.
As no significant histological findings were identified in the liver (or any other tissue), the organ weight finding may be considered nonadverse.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No macroscopic changs were observed in treated P generation rats as compared to control.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No microscopic changs were observed in treated P generation rats as compared to control.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: estrous cycle:
no effects observed
Description (incidence and severity):
No effect was observed on estrous cycle of P generation as compared to contorl
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
No effect was observed on sperm evalution of P generation male rats as compared to contorl
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect on Fertility, gestation, vaginal opening and preputial separation of treated P rats were observed as compared to control.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
155 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
water consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive function (sperm measures)
reproductive performance
Remarks on result:
other: No effect observed
Dose descriptor:
NOAEL
Effect level:
182 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
water consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive function (estrous cycle)
reproductive performance
Remarks on result:
other: No effect observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No effect on neurodevelopmental (Cohort 2) were observed in F1 male and femlae rats.

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
no effects observed
Description (incidence and severity):
No effect on developmental immune effects (Cohort 3) were observed in F1 male and femlae rats.

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
184 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
developmental neurotoxicity
developmental immunotoxicity
Remarks on result:
other: No effect observed
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
169 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
developmental neurotoxicity
developmental immunotoxicity
Remarks on result:
other: No effect observed

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specifiednot specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 155 mg/kg/day for male and 182 mg/kg bw for female P generation and 184 mg/kg/day for male and 169 mg/kg bw for female F1 generation when Crl:CD (Sprague-Dawley) male and female rats treated with 1,2-dichloroethane orally by drinking water.
Executive summary:

In a Extended one generation toxicity (EOGRT) study, Crl:CD (Sprague-Dawley) male and female rats treated with 1,2-dichloroethane in the concentration of 0 (vehicle), 50, 150, and 300 mg/kg bw/day orally by drinking water as per OECD 443. Decrease in body weight and body weight gain was observed in treated rats in P generation. As EDC in drinking water to have poor palatability; drinking water consumption was generally decreased, relative to Controls, in a dose-related manner. Similarly, No effect was observed on estrous cycle, sperm evaluation, Fertility, gestation, vaginal opening and preputial separation of treated P male and female rats as compared to control. In addition, Change in relative liver weight was observed in F0 female rats. As no significant histological findings were identified in the liver (or any other tissue), the organ weight change may be considered non adverse. No gross pathological and Histopathological changes were observed in treated male and female P rats. No Reproductive/developmental effects (Cohort 1), neurodevelopmental effects (Cohort 2), and developmental immune effects (Cohort 3) were observed in F1 male and female rats. Therefore, NOAEL was considered to be 155 mg/kg/day for male and 182 mg/kg bw for female P generation and 184 mg/kg/day for male and 169 mg/kg bw for female F1 generation when Crl:CD (Sprague-Dawley) male and female rats treated with 1,2-dichloroethane orally by drinking water.