4-ethylmorpholine

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

GLP study performed according to OECD Guideline 421. 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

Reference

Reference 1

Reference Type:

other: public database

Title:

Unnamed

Year:

2003

Reference 2

Reference Type:

other: public database

Title:

Unnamed

Year:

2003

Report date:

2003

Reference 3

Reference Type:

grey literature

Title:

Unnamed

Year:

2004

Reference 4

Reference Type:

publication

Title:

Toxicity to Reproduction

Author:

Japanese government

Year:

2005

Bibliographic source:

OECD SIDS Initial Assessment Report for SIAM 21 and OECD Agreed Conclusions

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

Test material information

Constituent 1

Reference substance name:

4-ethylmorpholine

EC Number:

202-885-0

EC Name:

4-ethylmorpholine

Cas Number:

100-74-3

Molecular formula:

C6H13NO

IUPAC Name:

4-ethylmorpholine

Test material form:

liquid

Details on test material:

- Alternative names of reference substance: Jeffcat NEM; N-ethylmorpholine; 4-ethylmorpholin; Morpholine, 4-ethyl-
- Molecular formula: C6H13NO
- Molecular weight: 115.17
- SMILES notation: CCN1CCOCC1
- InChl: InChI=1/C6H13NO/c1-2-7-3-5-8-6-4-7/h2-6H2,1H3

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2901P0

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: The test solution was kept in a refrigerator
- 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.

Test animals

Species:

rat

Strain:

other: Crj:CD(SD)IGS

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Crj:CD(SD)IGS rats bought from Charles River Japan, Inc
- Age at study initiation: 4 weeks old
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum):no data
- Water (e.g. ad libitum):no data
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

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 / concentrations

Remarks:

Doses / Concentrations:
0 (vehicle), 50, 150, 500 mg/kg bw/day
Basis:
nominal conc.

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

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No deaths were found in males of any group. One female at 500 mg/kg bw/day died on day 2 of lactation. 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.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
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.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No adverse effects on estrous cyclicity

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Not examined

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No effects on copulation index, fertility index, precoital interval, gestation length, gestation index and number of corpora lutea.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute and relative weights of the testes and epididymides in the group treated with this chemical were not different from the control group

GROSS PATHOLOGY (PARENTAL ANIMALS)
Necropsy revealed no changes related to the administration of this chemical.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Histopathological examination of reproductive organs revealed no abnormalities related to dosing.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Decreases in body weight gain and food consumption were detected in males of the 500 mg/kg group

2

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Decreases in body weight gain and food consumption were detected in females of the 150 and 500 mg/kg groups

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

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)

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.

Overall reproductive toxicity

Reproductive effects observed:

not specified

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.