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Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline with acceptable restrictions (non-GLP).
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
yes
Remarks:
Only 3 applications per week; no or only partial examination of oestrous cycle and sperm parameters.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
As described in guideline.
Route of administration:
dermal
Vehicle:
water
Details on exposure:
Dose volume: 1 mL/kg bw
Details on mating procedure:
As described in guideline.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
No data.
Frequency of treatment:
3/week (except during mating)
Details on study schedule:
P: 119 days of dosing
F1: 133 days of dosing
Remarks:
Doses / Concentrations:
0, 1, 10, 25%
Basis:
nominal in water
Remarks:
Doses / Concentrations:
0, 10, 100, 250 mg/kg bw
Basis:
nominal in water
No. of animals per sex per dose:
30 (P)
20/40 (male/female; F1)
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
As described in guideline.
Oestrous cyclicity (parental animals):
Not examined.
Sperm parameters (parental animals):
Weight and histopathology are missing.
Litter observations:
No individual weighing of pups.
Postmortem examinations (parental animals):
As described in guideline.
Postmortem examinations (offspring):
As described in guideline.
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
In the highest dose, body weights of both males and females in both treated generations were sporadically and not always statistically significant decreased compared to controls.
At necropsy organ weight differences in liver, lung, kidney and heart were observed in the F1 generation, but no pathological findings were associated with the affected organs.
Dose descriptor:
NOAEL
Remarks:
reprotox
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Remarks on result:
other: Generation: P, F1 (migrated information)
Dose descriptor:
NOAEL
Remarks:
dev tox
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Remarks on result:
other: Generation: F1, F2 (migrated information)
Dose descriptor:
NOEL
Remarks:
systemic
Effect level:
100 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Remarks on result:
other: Generation: P, F1 (migrated information)
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Changes in body weight and organ weights without associated pathological findings.
Remarks on result:
other: Generation: P, F1 (migrated information)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Dose descriptor:
NOAEL
Remarks:
development
Generation:
F1
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Remarks on result:
other: Generation: F1, F2 (migrated information)
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

In a two-generation reproduction study, groups of 30 weanling Fischer 344 rats of each sex 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 five deaths in the F1 adult males and females in the control and treatment groups were not considered to be compound-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 F0 and 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 dermal tested dose.

Further evidence for the lack of reproductive toxicity of alcohol ethoxylates has been provided by a range of subchronic oral feeding studies which investigated also any potential effects on the organs of the reproductive system (see Chapter 7.5). None of these studies revealed any adverse effects of exposure to AE on the reproductive system.

 

Based on the information above, even though application by the dermal route is not the first choice to investigate reproductive effects (see Chapter 7.1), conducting an oral two-generation reproductive toxicity study is scientifically not of high priority. In addition, data need aspects have to be balanced with animal welfare considerations.

However, a reproductive toxicity study on a structurally similar material, C14-15AE7 (CAS 68951-67-7) was conducted at dietary levels of 25, 50 and 250 mg/kg bw/day. The 2-generation study (Procter and Gamble Ltd., 1977: Long term reproduction and teratology study in rats with Neodol 45-7; unpublished report) did not show any potential for reproductive toxicity at the tested dose levels. The NOAEL for reproductive effects was greater than the highest tested dose of 250 mg/kg bw/day. Although the study was pre-GLP and not in full compliance with current OECD guidelines, the study provided sufficient information and was assessed to be scientifically reliable.

The comparable toxicokinetic and metabolic profiles, as well as their toxicological similarities for this and other toxicological endpoints, support the conclusion that insights from the reproductive toxicity study on higher ethoxylated AE are applicable to AE with an ethoxylation degree of 1-2.5.

With regard to animal welfare this read across should be considered to close the data gap in case that the presented reproductive toxicity study via the dermal route in combination with the oral subchronic repeated dose studies is regarded as not sufficient to cover this endpoint.


Short description of key information:
OECD 416, rat, 2-generation, dermal: not reprotoxic
Parental/F1: NOAELsystemic = 250 mg/kg bw/day; LOAELsystemic > 250 mg/kg bw/day
F1/2: NOAELrepro = 250 mg/kg bw/day; LOAELrepro > 250 mg/kg bw/day

Effects on developmental toxicity

Description of key information
OECD 416, rat, 2-generation, dermal: not teratogenic
Parental/F1: NOAELsystemic = 250 mg/kg bw/day; LOAELsystemic > 250 mg/kg bw/day
F1/2: NOAELdev = 250 mg/kg bw/day; LOAELdev > 250 mg/kg bw/day
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (non-GLP).
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
other: OECD 416
Deviations:
yes
Remarks:
Only 3 applications per week; no or only partial examination of oestrous cycle and spermatogenicity.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Fischer 344
Details on test animals and environmental conditions:
As described in guideline.
Route of administration:
dermal
Vehicle:
water
Details on exposure:
Dose volume: 1 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
As described in guideline.
Duration of treatment / exposure:
No data.
Frequency of treatment:
3/week (except during mating)
Duration of test:
From Day 0 of gestation until weaning.
Remarks:
Doses / Concentrations:
0, 1, 10, 25%
Basis:
nominal in water
Remarks:
Doses / Concentrations:
0, 10, 100, 250 mg/kg bw
Basis:
nominal in water
No. of animals per sex per dose:
30 (P)
20/40 (male/female; F1)
Control animals:
yes, concurrent vehicle
Maternal examinations:
As described in guideline.
Ovaries and uterine content:
As described in guideline.
Fetal examinations:
As described in guideline.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
In the highest dose, body weights of both males and females in both treated generations were sporadically and not always statistically significant decreased compared to controls.
At necropsy organ weight differences in liver, lung, kidney and heart were observed in the F1 generation, but no pathological findings were associated with the affected organs.
Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw/day (nominal)
Based on:
act. ingr.
Remarks on result:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

In a two-generation reproduction study, groups of 30 weanling Fischer 344 rats of each sex 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. The complete study protocol has been described above. No compound related effects on litter size, number of live pubs and sex ratio of pups in the F1 and F2 generations were observed. Low incidences of foetal malformations were observed, but these were not dose related and considered to be of spontaneous nature. At necropsy, no effects were observed in the F1 pups. In the F2 pups, a significantly higher carcass weight in the females of the 250 mg/kg bw/day dose group was noted and some minor organ weight differences. Due to the lack of a dose-response and no associated morphological findings, these effects were considered to be of no toxicological significance. It was concluded that dermal application of C9-11AE6 to rats did not induce any adverse effects on the growth and development of the offspring during two generations. The NOAEL of C9-11AE6 with respect to developmental and teratogenic toxicity can be assumed to be higher than the highest dose level dermally applied in this study (i.e., 250 mg/kg bw/day).

 

Based on the information above, even though application by the dermal route is not the first choice to investigate reproductive effects (see Chapter 7.1), conducting an oral developmental toxicity study is scientifically not of high priority. In addition, data need aspects have to be balanced with animal welfare considerations.

However, a reproductive toxicity study on a structurally similar material, C14-15AE7 (CAS 68951-67-7)was conducted at dietary levels of 25, 50 and 250 mg/kg bw/day. The 2-generation study (Procter and Gamble Ltd., 1977: Long term reproduction and teratology study in rats with Neodol 45-7; unpublished report) did not show any potential for reproductive toxicity at the tested dose levels. The NOAEL for reproductive effects was greater than the highest tested dose of 250 mg/kg bw/day. Although the study was pre-GLP and not in full compliance with current OECD guidelines, the study provided sufficient information and was assessed to be scientifically reliable.

The comparable toxicokinetic and metabolic profiles, as well as their toxicological similarities for this and other toxicological endpoints, support the conclusion that insights from the reproductive toxicity study on higher ethoxylated AE are applicable to AE with an ethoxylation degree of 1-2.5.

With regard to animal welfare this read across should be considered to close the data gap in case that the presented reproductive toxicity study via the dermal route in combination with the oral subchronic repeated dose studies is regarded as not sufficient to cover this endpoint.

Justification for classification or non-classification

According to the classification criteria of Directive 67/548/EEC and Regulation (EC) No 1272/2008 the substance does not need to be classified for toxicity to reproduction. No data available on breastfed babies.