4-methylmorpholine 4-oxide, monohydrate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From September 9, 1981 through September 28, 1981

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

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 4-oxide, monohydrate

EC Number:

231-391-8

EC Name:

4-methylmorpholine 4-oxide, monohydrate

Cas Number:

7529-22-8

Molecular formula:

C5H11NO2

IUPAC Name:

4-methyl-4λ⁵-morpholin-4-one

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4236-43-5, Order #J-85
- Substance type: yellow liquid
- Purity: responsibility of the sponsor. It is confirmed by the Sponsor that the test has been performed with a 50% aqueous solution.
- Stability: There was no apparent change in the physical state of the test article during administration
- Other: Specific gravity = 1.136 g/mL

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Blue Spruce Farms, Altamont, New York
- Weight at study initiation: 180 - 360 grams after fasting. The weight variation in animals or between groups did not exceed +/- 20%
- Housing: Separate isolation by test system; rats were housed individually in stainless steel wire mesh cages. Size in accordance with Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Resources, National Research Council.
- Diet (e.g. ad libitum): Wayne Lab Blox, ad libitum, checked daily and added or replaced as needed. Feeders are designed to reduce soiling, briding, and scattering
- Water (e.g. ad libitum): Availability - fresh tap water, fit for human consumption, ad libitum, using an automatic watering system supplied by Edstrom Industries Inc., Waterford, Wisconsin
- Acclimation period: Five days
- Fasting period before study: 18 hours

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

7000, 8000, 9000 and 10000 mg/kg

No. of animals per sex per dose:

Five

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed approximately at one, two, four and twenty-four hours after dosing and twice daily for fourteen days for pharmacotoxic, CNS effects and mortality. On the seventh and fourteenth day body weights were recorded.
- Necropsy of survivors performed: yes: The surviving rats were sacrificed by CO2 inhalation and a gross necropsy performed.

Statistics:

no details

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

9 200 mg/kg bw

Based on:

test mat.

95% CL:

> 8 200 - <= 10 300

Effect levels 2

Sex:

male

Dose descriptor:

LD50

Effect level:

9 800 mg/kg bw

Based on:

test mat.

95% CL:

> 8 800 - <= 10 900

Effect levels 3

Sex:

female

Dose descriptor:

LD50

Effect level:

9 300 mg/kg bw

Based on:

test mat.

95% CL:

> 7 800 - <= 11 200

Mortality:

None of the animals died at the 7000 mg/kg dose level, two of the ten died at the 8000 mg/kg dose level (2 females), three of ten died at the 9000 mg/kg dose level (1 male, 2 females) and seven of ten died at the 10000 mg/kg dose level (3 males and 4 females).

Clinical signs:

other: Diarrhea, piloerection, abnormal gait, abnormal stance, decreased body tone, decreased activity and orange discoloration around the nose and genital areas.

Gross pathology:

Necropsy revealed distended fluid-filled stomachs and intestines (clear, tan, green, white or orange), mottled lungs, darkened thymuses and darkened lymph nodes. Terminal necropsy revealed no visible lesions in any of the remaining rats.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The calculated acute oral LD50 for male and female rats treated with the substance, was determined to be 9200 mg/kg with 95% confidence limits of 8200 to 10300 mg/kg. The test solution used was a 50% aqueous solution of NMMO. The LD50 of the pure NMMO is therefore considered to be 4600 mg/kg. Based on the study results and the criteria of the CLP Regulation, this substance should not be classified for oral toxicity.

Executive summary:

In an acute oral toxicity study which was performed equivalent/similar to OECD TG 401, groups of five Sprague-Dawley rats/sex were given a single oral dose of 4-methylmorpholine 4-oxide (50% aqueous solution) by oral gavage at doses of 7000, 8000, 9000 and 10000 mg/kg bw. Animals were then observed for 14 days.

None of the animals died at the 7000 mg/kg dose level, two of the ten died at the 8000 mg/kg dose level (2 females), three of ten died at the 9000 mg/kg dose level (1 male, 2 females) and seven of ten died at the 10000 mg/kg dose level (3 males and 4 females). Necropsy revealed distended fluid-filled stomachs and intestines (clear, tan, green, white or orange), mottled lungs, darkened thymuses and darkened lymph nodes. Terminal necropsy revealed no visible lesions in any of the remaining rats. Clinical signs included Diarrhea, piloerection, abnormal gait, abnormal stance, decreased body tone, decreased activity and orange discoloration around the nose and genital areas.

The oral LD50 was calculated to be 9800 mg/kg bw for males and 9300 mg/kg bw for females. The combined oral LD50 was calculated to be 9200 mg/kg bw/day.

As a 50% aqueous solution is used, the combined LD50 for the pure NMMO is considered to be 4600 mg/kg bw. Based on the results of this study and according to the criteria of the CLP Regulation, the substance should not be classified for acute oral toxicity.

This acute oral study is classified as acceptable. It satisfies the guideline requirements for an acute oral toxicity study. Dose levels exceeded the current standards of oral toxicity testing.