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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
GLP study; considered as reliable by experts groups of HERA and CIR
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1985
Report date:
1985
Reference Type:
publication
Title:
Safety assessment of alkyl PEG ethers as used in cosmetics.
Author:
Cosmetic Ingredient Review (CIR) Expert Panel
Year:
2012
Bibliographic source:
Int J Toxicol. 2012 Sep-Oct;31(5 Suppl):169S-244S
Reference Type:
publication
Title:
Human & Environmental Risk Assessment on Alcohol Ethoxylates
Author:
HERA Substance Team
Year:
2009
Bibliographic source:
Web Publication
Reference Type:
publication
Title:
Acute, Subchronic, and Reproductive Toxicity of a Linear Alcohol Ethoxylates Surfactant in the Rat
Author:
Gingell and Lu
Year:
1991
Bibliographic source:
Journal of the American College of Toxicology, Volume 10, Number 4, page 477-486

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
yes
Remarks:
3 applications per week / no treatment during mating
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
68439-46-3
EC Number:
614-482-0
Cas Number:
68439-46-3
IUPAC Name:
68439-46-3
Specific details on test material used for the study:
Test material: C9-11 pareth 6 (mixture of C9-11 alkyl alcohol with 6 ethoxylation unit)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
dermal
Vehicle:
water
Details on exposure:
Dose volume: 1 mL/kg bw
Details on mating procedure:
1:1 ration of cohabitation; avoid of sibling or half-sibling mating
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
F0 generation: 119 days prior to mating
F1 generation: 133 days prior to mating
Frequency of treatment:
3/week (except during mating)
Details on study schedule:
P: 119 days of dosing
F1: 133 days of dosing
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
dermal exposure to 1mL/kg of 0% test material (w/v) in water
Dose / conc.:
1 mg/kg bw/day
Remarks:
dermal exposure to 1mL/kg of 10% test material (w/v) in water
Dose / conc.:
100 mg/kg bw/day
Remarks:
dermal exposure to 1mL/kg of 10% test material (w/v) in water
Dose / conc.:
250 mg/kg bw/day
Remarks:
dermal exposure to 1mL/kg of 25% test material (w/v) in water
No. of animals per sex per dose:
F0: 30 males and 30 females
F1: 20 males and 20 females
Control animals:
yes, concurrent vehicle
Details on study design:
The F0 groups, consisting of 30 males and 30 females, were exposed dermally to 1 mL/kg of 0%, 1%, 10% or 25% w/v aqueous test material for 119 days prior to mating. The test site was shaved, but the application sites were not covered. The test material was not applied during mating to avoid ingestion. Among the F1 generation, groups of 20 males and 20 females per test group were mated. The male rats of both generations were killed following mating.
On day 4 of lactation, any litter with more than 10 pups was culled to 10.

Examinations

Parental animals: Observations and examinations:
Weekly body weight investigation of males and females up to the time of mating; weekly body weight investigation of females during gestation and lactation;
Sperm parameters (parental animals):
Enumeration of sperm heads and LDH-X activity of left testes of each F0 and F1 male.
Litter observations:
- Litter weight investigation on days 1, 4,7,21 and 28 of lactation; Individual body weight of pups on day 28 of lactation
- At parturition litter size, sex of pups, number of live and sillborn pups.
- Daily observation of pups mortality and physical abnormalities.
Postmortem examinations (parental animals):
Gross necropsies on all F0 and F1 parents; histopathological examinations included all reproductive organs, all lesions in F0 parents; Organ weights of the reproductive organs, liver, spleen, heart, kidney and lung in F1 parents.
Postmortem examinations (offspring):
Gross necropsies, histopathological examinations and organ weights on selected F1 and F2 pups (5/sex/dose)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
No irritation was observed for any of the animals, but dry flaking skin was observed in the 10% and 25% dose groups.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Five death was observed in the F1 adult in the ctronol and treatment group, not treatment related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Minimal decrease at 25%.
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Description (incidence and severity):
No effects regarding organ weights, mating indices, fertility indices, or mean gestational length.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive performance
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect up to the highest dose level
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect up to the highest dose level

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
No irritation was observed for any of the animals, but dry flaking skin was observed in the 10% and 25% dose groups.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Five death in the P1/F1 animals in control and treatment groups.
Body weight and weight changes:
effects observed, non-treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Weight change in liver, lung, kidney and heart in P1/F1 animals

Reproductive function / performance (P1)

Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Description (incidence and severity):
No effects regarding organ weights, mating indices, fertility indices, or mean gestational length.

Effect levels (P1)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive performance
Effect level:
>= 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect up to the highest dose level
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect up to the highest dose level

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
No irritation was observed for any of the animals, but dry flaking skin was observed in the 10% and 25% dose groups.
Mortality / viability:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Five death in the P1/F1 animals in control and treatment groups.
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Weight change in liver, lung, kidney and heart in P1/F1 animals.
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Generation:
F1
Effect level:
>= 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect up to the highest dose level

Results: F2 generation

Effect levels (F2)

Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Generation:
F2
Effect level:
>= 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect was observed up to the highest dose level

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Executive summary:

In a two-generation reproduction study, Fischer 344 rats were dermally exposed to 1 mL/kg bw C9-11AE6 (CAS 68439-46-3) at concentrations of 0, 1, 10 or 25% w/v three times a week except during the mating periods. This treatment equals exposure levels of about 0, 10, 100 and 250 mg/kg bw/day. No mortalities were observed in the parental generation, and the deaths in the P1/F1 adult males and females in the control and treatment groups were not considered to be treatment related. In the highest dose group, body weights of both males and females in both treated generations were sporadically decreased compared to controls. There was no effect on maternal body weight during gestational and lactational periods in both generations. At necropsy organ weight differences in liver, lung, kidney and heart were observed in the F1 generation. However no pathological findings were associated with these affected organs. There were no compound-related effects on mating and fertility indices and mean gestational length in both generations. No effects on testicular weights, sperm counts and LDH-X activities in P0 and P1/F1 male adults were observed. Macroscopic and microscopic examination of the reproductive organs did not reveal significant differences in the treated groups compared to the controls. Based on these observations the NOAEL for reproductive and developmental toxicity can be established at 250 mg/kg bw/day, the highest dermally tested dose.