Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
other justification
Justification for data waiving:
other:
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 study available
Additional information

In accordance with Annex XI(3) of the REACH regulation, studies on reproductive and developmental toxicity of the substance are not required, based on no significant exposure, as described in the exposure scenarios of the Chemical Safety Report.

A developmental toxicity study conducted with NPE-9 suggests no effects at doses which are not maternally toxic.

Exposure in industrial settings

The identified uses of this substance include manufacturing as well as formulation and mixing in industrial settings. These activities occur in closed batch systems with little exposure for workers. As presented in Chapters 10.1 and 10.2, the RCR for all relevant exposure routes are very low, ranging from 0.001 - 0.037. No significant risk for workers is therefore expected under the given operational conditions and risk management measures.

Consumer exposure

There are no consumer uses of the substance.

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles, acceptable for assessment.
Principles of method if other than guideline:
Mol:WIST rats, 11 weeks of age, were mated. Mated females received NPE-9 (commercial formulation with an average ethoxylation grade of 9) by gavage or skin application from Gestation Day 6 - 15 or 1 -20 (only 500 mg/kg bw/day per oral). On Day 21, the rats were weighed, sacrificed and necropsied. The following parameters were recorded: weight of the intact uterus and ovaries, number of corpora lutae, implantation and fetuses, live and dead. The fetuses were weighed, their sex determined and they were examined for gross external malformations. Half of the fetuses were examined for skeletal abnormalities. The remaining fetuses were fixed in Bouins solution and sectioned. Weight of dams, sex ration of fetuses and pre- and post-implantation losses were calculated.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Mol: WIST
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Molle-gards Breeding Center Ltd., Denmark
- Age at study initiation: 11 weeks
- Housing: stainless steel wire cages
- Diet (e.g. ad libitum): powdered chow (Chow 101)
- Water (e.g. ad libitum): acidified water, citric acid, pH 3.5, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 1°C
- Humidity (%): 60 +/-5°C
- Air changes (per hr): 6-8
- Photoperiod (hrs dark / hrs light): 12:12
Route of administration:
other: oral and dermal
Vehicle:
water
Details on exposure:
ORAL
Application by gavage of the substance diluted in water.

DERMAL
The substance was injected into a porous dressing placed on shaved skin (3 x 6 cm) and covered by tape (Fixomul).
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Gestation Day 6 to 15
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 50, 250, and 500 mg/kg bw/day
Basis:
nominal conc.
oral application
Remarks:
Doses / Concentrations:
0, 50 and 500 mg/kg bw/day
Basis:
nominal conc.
dermal application
No. of animals per sex per dose:
19-25
Maternal examinations:
Bodyweight of mated females on Days 1, 6, 9, 12, 15 and 21.

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Other: Number of fetuses, live and dead; ovary weight
Fetal examinations:
- Fetus weight and sex
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
Statistics:
Student's t-test was performed on bodyweight F0, weight gain F0, litter size, sex ratio, bodyweight F1, mean implantation weight of the intact uteri (inclusive ovaries), pre-and post-implantation loss.
The 'Qiock tes-chi-square" was used for special parameters in the teratogenicity test (Mainland 1963).
Indices:
Weight of dams, sex ration of fetuses and pre- and post-implantation losses were calculated.
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The dams given 250 mg NPE-9/kg bw/day orally on Days 6-15 and 500 mg/kg bw/day on Days 6-15 and 1-20 exhibited a statistically significant decrease in weight gain. All rats given epicutaneous doses, including controls, exhibited a marked decrease in bodyweight and weight gain during the treatment.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A concomitant decrease in food consumption was observed in dams exposed to 500 mg/kg bw/day as compared to control.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
The dams given 250 mg NPE-9/kg bw/day orally on Days 6-15 and 500 mg/kg bw/day on Days 6-15 and 1-20 exhibited a statistically significant decrease in weight gain. A concomitant decrease in food consumption was observed in dams exposed to 500 mg/kg bw/day as compared to controls. All rats given epicutaneous doses, including controls, exhibited a marked decrease in bodyweight and weight gain during the treatment.
Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
A slight, but statistically significant, lower average litter size was observed at 250 mg/kg bw/day and an increase in pre-implantation loss at 250 and 500 (Days 6-15) mg/kg bw/day. The animals given the highest epicutaneous dose exhibited higher reproduction as compared to controls (increased litter size and decreased post-implantation loss).
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
A slight, but statistically significant, lower average litter size was observed at 250 mg/kg bw/day and an increase in pre-implantation loss at 250 and 500 (Days 6-15) mg/kg bw/day. The animals given the highest epicutaneous dose exhibited higher reproduction as compared to controls (increased litter size and decreased post-implantation loss).
Early or late resorptions:
not examined
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
The dams given 250 mg NPE-9/kg bw/day orally on Days 6-15 and 500 mg/kg bw/day on Days 6-15 and 1-20 exhibited a statistically significant decrease in weight gain. A concomitant decrease in food consumption was observed in dams exposed to 500 mg/kg bw/day as compared to controls. All rats given epicutaneous doses, including controls, exhibited a marked decrease in bodyweight and weight gain during the treatment.
Sporadic, not dose-related, changes in reproduction parameters were observed in the rats treated orally with NPE-9. A slight, but statistically significant, lower average litter size was observed at 250 mg/kg bw/day and an increase in pre-implantation loss at 250 and 500 (Days 6-15) mg/kg bw/day.
The animals given the highest epicutaneous dose exhibited higher reproduction as compared to controls (increased litter size and decreased post-implantation loss).
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Abnormalities:
effects observed, treatment-related
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

In rats given NPE-9 orally, a statistically significant dose-related increase in extra ribs and rudiments of ribs was noted. In addition, an increased incidence in fetuses showing slightly dilated pelvic cavity was observed at 500 mg/kg bw/day (Day 1 - 20). When given epicutaneously, NPE-9 had no effects on skeletal and solt tissues. An increased incidence of extra ribs was seen at 50 mg/kg bw/day but not at 500 mg/kg bw/day (epicutaneous).
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Increase in extra ribs and rudiments of ribs, increased incidence in fetuses showing slightly dilated pelvic cavity (at 500 mg/kg bw/day)
Remarks on result:
other: following oral exposure
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on skeletal and solt tissues
Remarks on result:
other: following epicutaneous exposure
Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
other: skeletal: ribs and pelvic cavity
Description (incidence and severity):
Following oral exposure: Increase in extra ribs and rudiments of ribs, increased incidence in fetuses showing slightly dilated pelvic cavity (at 500 mg/kg bw/day)
Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
skeletal: rib
Description (incidence and severity):
An increased incidence of extra ribs was seen at 50 mg/kg bw/day but not at 500 mg/kg bw/day (epicutaneous).
Key result
Developmental effects observed:
no
Conclusions:
Under the study conditions, the NOEL for NPE-9 was 50 mg/kg bw/day (Days 6 -15) when given orally. Higher doses exerted reproductive toxicity effects probably due to maternal toxicity. Epicutaneaius doses of NPE-9 had no effect.
Executive summary:

Male and female Mol:WIST rats, 11 weeks of age, were mated. Mated females received NPE-9 (commercial formulation with an average ethoxylation grade of 9) by gavage (0, 50, 250 and 500 mg/kg bw/day) or skin application (0, 50 and 500 mg/kg bw/day) from Gestation Day 6 - 15 or 1 -20 (only 500 mg/kg bw/day per oral). Mated females were weighed on Days 1, 6, 9, 12, 15 and 21. On Day 21, the rats were sacrificed and necropsied. The following parameters were recorded: weight of the intact uterus and ovaries, number of corpora lutae, implantation and fetuses, live and dead. The fetuses were weighed, their sex determined and they were examined for gross external malformations. Half of the fetuses were examined for skeletal abnormalities. The remaining fetuses were fixed in Bouins solution and sectioned. Weight of dams, sex ration of fetuses and pre- and post-implantation losses were calculated.

The dams given 250 mg NPE-9/kg bw/day orally on Days 6-15 and 500 mg/kg bw/day on Days 6-15 and 1-20 exhibited a statistically significant decrease in weight gain. A concomitant decrease in food consumption was observed in dams exposed to 500 mg/kg bw/day as compared to controls. All rats given epicutaneous doses, including controls, exhibited a marked decrease in bodyweight and weight gain during the treatment. Sporadic, not dose-related, changes in reproduction parameters were observed in the rats treated orally with NPE-9. A slight, but statistically significant, lower average litter size was observed at 250 mg/kg bw/day and an increase in pre-implantation loss at 250 and 500 (Days 6-15) mg/kg bw/day. The animals given the highest epicutaneous dose exhibited higher reproduction as compared to controls (increased litter size and decreased post-implantation loss). In rats given NPE-9 orally, a statistically significant dose-related increase in extra ribs and rudiments of ribs was noted. In addition, an increased incidence in fetuses showing slightly dilated pelvic cavity was observed at 500 mg/kg bw/day (Day 1 - 20). When given epicutaneously, NPE-9 had no effects on skeletal and solt tissues. An increased incidence of extra ribs was seen at 50 mg/kg bw/day but not at 500 mg/kg bw/day (epicutaneous).

Under the study conditions, the NOEL for NPE-9 was 50 mg/kg bw/day (Days 6 -15) when given orally. Higher doses exerted reproductive toxicity effects probably due to maternal toxicity. Epicutaneous doses of NPE-9 had no effect (Meyer et al., 1988).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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
Additional information

Male and female Mol:WIST rats, 11 weeks of age, were mated. Mated females received NPE-9 (commercial formulation with an average ethoxylation grade of 9) by gavage (0, 50, 250 and 500 mg/kg bw/day) or skin application (0, 50 and 500 mg/kg bw/day) from Gestation Day 6 - 15 or 1 -20 (only 500 mg/kg bw/day per oral). Mated females were weighed on Days 1, 6, 9, 12, 15 and 21. On Day 21, the rats were sacrificed and necropsied. The following parameters were recorded: weight of the intact uterus and ovaries, number of corpora lutae, implantation and fetuses, live and dead. The fetuses were weighed, their sex determined and they were examined for gross external malformations. Half of the fetuses were examined for skeletal abnormalities. The remaining fetuses were fixed in Bouins solution and sectioned. Weight of dams, sex ration of fetuses and pre- and post-implantation losses were calculated.

The dams given 250 mg NPE-9/kg bw/day orally on Days 6-15 and 500 mg/kg bw/day on Days 6-15 and 1-20 exhibited a statistically significant decrease in weight gain. A concomitant decrease in food consumption was observed in dams exposed to 500 mg/kg bw/day as compared to controls. All rats given epicutaneous doses, including controls, exhibited a marked decrease in bodyweight and weight gain during the treatment. Sporadic, not dose-related, changes in reproduction parameters were observed in the rats treated orally with NPE-9. A slight, but statistically significant, lower average litter size was observed at 250 mg/kg bw/day and an increase in pre-implantation loss at 250 and 500 (Days 6-15) mg/kg bw/day. The animals given the highest epicutaneous dose exhibited higher reproduction as compared to controls (increased litter size and decreased post-implantation loss). In rats given NPE-9 orally, a statistically significant dose-related increase in extra ribs and rudiments of ribs was noted. In addition, an increased incidence in fetuses showing slightly dilated pelvic cavity was observed at 500 mg/kg bw/day (Day 1 - 20). When given epicutaneously, NPE-9 had no effects on skeletal and solt tissues. An increased incidence of extra ribs was seen at 50 mg/kg bw/day but not at 500 mg/kg bw/day (epicutaneous). Under the study conditions, the NOEL for NPE-9 was 50 mg/kg bw/day (Days 6 -15) when given orally. Higher doses exerted reproductive toxicity effects probably due to maternal toxicity. Epicutaneous doses of NPE-9 had no effect (Meyer et al., 1988).

Justification for classification or non-classification

No direct reproductive or toxicity data available on NPEO.