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Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
The original study report is in Japanese language, although the figures and tables are in English. An English summary is available from the Japanese authorities and an extensive summary is present in the OECD HPV program files.

Data source

Referenceopen allclose all

Reference Type:
other: public database
Title:
Unnamed
Year:
2003
Reference Type:
other: public database
Title:
Unnamed
Year:
2003
Report date:
2003
Reference Type:
grey literature
Title:
Unnamed
Year:
2004
Reference Type:
secondary source
Title:
Unnamed
Year:
2005
Report date:
2007

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
4-ethylmorpholine
EC Number:
202-885-0
EC Name:
4-ethylmorpholine
Cas Number:
100-74-3
IUPAC Name:
4-ethylmorpholine
Specific details on test material used for the study:
- Name of test material (as cited in study report): N-ethylmorpholine
- Molecular formula (if other than submission substance): C6 H13 N O
- Molecular weight (if other than submission substance): 115.18
- Smiles notation (if other than submission substance): CCN1CCOCC1
- InChl (if other than submission substance): InChI=1/C6H13NO/c1-2-7-3-5-8-6-4-7/h2-6H2,1H3
- Analytical purity: equal or more than 99%
- Impurities (identity and concentrations): 0.05% as moisture
- Lot/batch No.: 2901P0
- Stability under test conditions: The test solution was prepared and diluted to dosing concentrations by injection solvent every week. The diluted solution was confirmed to be stable for 8 days.
- Storage condition of test material: The test solution was kept in a refrigerator

Test animals

Species:
rat
Strain:
other: Crj:CD(SD)IGS
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animals: Four weeks old Crj:CD(SD)IGS rats bought from Charles River Japan, Inc. They were put in quarantine and acclimatization for 7 days before use.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Vehicle: water for injection.
The test solution was prepared and diluted to dosing concentrations by injection solvent every week.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The dosing solutions were confirmed to be stable.
Duration of treatment / exposure:
Males: 42 days
Females: from 14 days before mating to day 3 of lactation
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
vehicle
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Positive control:
None.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes, on day 1, 7, 14, 21, 28, 35, 42, 43 (males). Females: on day 1, 7, 14 pre-mating, on day 0, 7, 14, 20 of pregnancy and on day 0 and 4 of lactation.

FOOD CONSUMPTION: Yes, on days 1-2, 7-8, 14-15, 29-30, 35-36, 41-42 (males). Females on days 1-2, 7-8, 14-15 pre-mating, on days 0-1, 7-8, 14-15, 20-21 of pregnancy and on days 3-4 of lactation.

ORGAN WEIGHTS: Yes

Oestrous cyclicity (parental animals):
mean length of estrous cycle during treatment period and pre-treatment period, number of animals showing 4-day cycle during pre-treatment period, changes of estrous cycle after treatment, mean times of vaginal estrus during mating period.
Sperm parameters (parental animals):
absolute and relative weights of testes and epididymides.
Litter observations:
STANDARDISATION OF LITTERS
No pups were discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, weight gain
Postmortem examinations (parental animals):
Examined
Postmortem examinations (offspring):
Examined
Statistics:
Methods by Dunnett, bartlett, Fischer, Mann-Whitney
Reproductive indices:
copulation index, fertility index, gestation index, indexes for implantation, delivery
Offspring viability indices:
indexes for birth and live birth

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Tremor was observed in the female which died, and transient salivation after dosing was observed in males and females at 150 mg/kg bw/day and higher.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
No deaths were found in males of any group. One female at 500 mg/kg bw/day died on day 2 of lactation.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decrease in body weight gain accompanied by reduced food consumption was detected in males at 500 mg/kg bw/day and females at 150 mg/kg bw/day and higher.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decrease in body weight gain accompanied by reduced food consumption was detected in males at 500 mg/kg bw/day and females at 150 mg/kg bw/day and higher.
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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Histopathological examination of reproductive organs revealed no abnormalities related to dosing.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No adverse effects on estrous cyclicity
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
No effects on copulation index, fertility index, precoital interval, gestation length, gestation index and number of corpora lutea.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not examined

Details on results (F1)

Slight decreases in numbers and rate of implantation were detected in the 500 mg/kg group. There were, however, no adverse effects on estrous cycle, copulation, fertility, gestation length, gestation index or number of corpora lutea. Slight decreases in numbers of pups and numbers of live pups, presumably related to decrease in implantation, were detected in the 500 mg/kg group. There were no treatment-related changes in the body weight,
external appearance, general conditions or necropsy findings in offspring of rats.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed at highest dose tested.

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
The NOAELs for general toxicity in parent animals are considered to be 150 mg/kg bw/day in males and 50 mg/kg bw/day in females, based on reduced body weight gain and food consumption. The NOAEL for reproductive and developmental toxicity is considered to be 500 mg/kg bw/day.