4-methylmorpholine

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-10-03 - 1990-11-06

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-methylmorpholine

EC Number:

203-640-0

EC Name:

4-methylmorpholine

Cas Number:

109-02-4

Molecular formula:

C5H11NO

IUPAC Name:

4-methylmorpholine

Test material form:

liquid

Specific details on test material used for the study:

- Name of test material (as cited in study report): 6398-24-20, Project #90-005
- Appearance: clear colorless liquid
- Purity: responsibility of the sponsor
- Stability: there was no apparent change in the physical state of the test article during administration
- Other: Specific gravity: 0.92 g/mL; pH 10.8 (taken from MSDS)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, inc., Wilmington, Massachusetts, USA
- Age at study initiation: young adults
- Mean weight at study initiation (n=5 per group):
Males: 380.8 g (200 mg/kg dose group), 393.4 g (400 mg/kg dose group), 379.2 g (500 mg/kg dose group), 385.8 g (1000 mg/kg dose group), 344.6 g (1500 mg/kg dose group), 382.8 g (2000 mg/kg dose group)
Females: 221.6 g (200 mg/kg dose group), 233.4 g (400 mg/kg dose group), 226.2 g (500 mg/kg dose group), 224.8 (1000 mg/kg dose group), 244.4 g (1500 mg/kg dose group)
- Housing: Rats housed individually in stainless steel 1/2 wire mesh cages, sized in accordance with the Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council
- Diet (e.g. ad libitum): Wayne Teklad Lab Blox, ad libitum, checked daily and added or replaced as needed. Feeders are designed to reduce soiling, bridging, and scattering
- Water (e.g. ad libitum): Availability - fresh tap water, ad libitum
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C ± 3°C
- Humidity (%): 30 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Maximum dose volume did not exceed 10 ml/kg bw.

Doses:

Dose-range-finding study: 500, 2500 and 5000 mg/kg
Definitive LD50 study: 200, 400, 500, 1000, 1500 and 2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Observations:
Dose-range-finding study: the rats were observed at approximately 1, 4, 24, 48 and 72 hours after dosing for pharmacological and toxicological effects
Definitive LD50: The rats were observed at approximately 1, 4 and 24 hours after dosing and once daily through Day 14 for pharmacological and toxicological effects. Viability was checked daily. Body weights were recorded on Days 0, 7 and 14 or when found dead. All remaining rats were sacrificed by CO2 inhalation and gross necropsy performed.

Statistics:

LD50 determinations were performed via Litchfield and Wilcoxon on Pharmacological Calculations System, version 4.1.

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 442.3 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 137 - <= 1 829.4

Effect levels 2

Sex:

male

Dose descriptor:

LD50

Effect level:

1 723.2 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 454.9 - <= 2 040.9

Effect levels 3

Sex:

female

Dose descriptor:

LD50

Effect level:

1 212.4 mg/kg bw

Based on:

test mat.

95% CL:

>= 933.9 - <= 1 574.1

Mortality:

None of the animals died at 200, 400 or 500 mg/kg dose levels. One (female) of ten animals died at the 1000 mg/kg dose level. Five (4 females, 1 male) of ten died at the 1500 mg/kg dose level and nine (5 females, 4 males) of ten animals died at the 2000 mg/kg dose level.

Clinical signs:

other: Signs included decreased activity, piloerection, salivation, abnormal gait, abnormal stance, ptosis, chromodacryorrhea, dyspnea and convulsions.

Gross pathology:

Necropsy of the animals dying on study revealed distended and/or fluid filled stomachs and intestines, dark liver, dark pitted, mottled and/or pale kidneys and fluid filled uterine horns. Terminal necropsy of the remaining animals revealed mottled kidneys.

Any other information on results incl. tables

Results dose range study:

Signs observed included decreased activity, piloerection, salivation, abnormal gait, abnormal stance, ptosis, chromodacryorrhea, dyspnea and convulsions. One of two animals died at the 500 mg/kg dose level. Two of two animals died at both the 2500 and 5000 mg/kg dose levels. Based upon these results, a definitive LD50 test was performed.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based on the results from the Acute Exposure Oral Toxicity study in rats, the definitive acute oral LD50 in males and females for this substance was determined to be 1442.3 mg/kg with 95% confidence limits of 1137.0 to 1829.4 mg/kg. The substance is considered classified as acute oral toxicant category 4 according to the criteria laid down in the CLP Regulation.