4-methylmorpholine 4-oxide, monohydrate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 30 to May 14, 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

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 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Skin was abraded before exposure to the test substance.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

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): 4236-40-5
- Substance type: Yellow liquid
- Storage condition of test material: Room temperature
- Purity: 50% aqueous solution
- Other: Specific gravity: 1.136

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dutchland Laboratories, Inc., Denver, Pennsylvania
- Age at study initiation: Young adults
- Weight at study initiation: males: 2.8 to 2.9 kilograms; females: 3.4 to 3.9 kilograms
- Housing: Suspended stainless steel, animals individually housed
- Diet (e.g. ad libitum): Purina Rabbit Chow, ad libitum
- Water (e.g. ad libitum): Automatic watering system, ad libitum Municipal water supply (Elizabethtown Water Co.)
- Acclimation period: 38 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17,8°C - 20,6 °C (64-69°F)
- Humidity (%): monitored daily, no more details specified
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: trunk (dorsal and ventral surface and sides from scapular to pelvic area)
- % coverage: at least 20% of the body surface area
- Type of wrap if used: The substance was applied directly onto the exposed skin of the animal, and spread evenly over the entire area. A layer of 8-ply gauze was then wrapped around the animal to cover the application site. The animal was then wrapped in an impervious plastic sleeve, designed to contain the test material without leakage or undue pressure. The sleeve was secured with masking tape and Elizabethan collars were placed on all animals.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Following approximately 24 hours of exposure, wrappings were removed and the test site wipped free of excess test material. After 30 minutes, dermal observations were made.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 8000 mg/kg at a dose volume of 7.0 mL/kg

Duration of exposure:

24 hours

Doses:

8000 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
- Frequency of observations and weighing:
viability check: twice daily
observations of pharmacologic and toxicologic signs: approximately 1, 2, and 4 hours after dosing and daily thereafter for fourteen days
body weights: pre-dose, at the time of clipping (weights used for calculation of doses), days 7 and 14
skin irritation: approx. 30 min after removal of the occlusive wrapping and scored after Draize
- Necropsy of survivors performed: yes: all animals surviving at termination of the observation period (day 14) were killed by an intravenous overdose of sodium pentabarbital and examined grossly. All abnormalities were recorded but no tissues were saved

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 8 000 mg/kg bw

Based on:

test mat.

Mortality:

All of the animals survived the fourteen-day post-dose period.

Clinical signs:

other: Soft stool, fecal staining and staining of the ano-genital area were noted sporadically in single animals on Days 1 and 2. Several animals exhibited nasal discharge between Days 4 and 14.

Gross pathology:

Observations made at necropsy were similar to those seen in control animals in the laboratory or were considered to represent normal physiologic variations.

Other findings:

Irritation: after 24h animals exhibited well-defined or moderate to severe erythema, generally with very slight or slight edema.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

All animals survived the fourteen-day post-dose period. The LD50 value of the substance is greater than 8000 mg/kg. As a 50% aqueous solution is used, the LD50 for the pure NMMO is considered to be greater than 4000 mg/kg.
Based on the results of this study and according to the criteria of the CLP Regulation, the substance should not be classified for acute dermal toxicity.

Executive summary:

In an acute dermal toxicity study performed equivalent or similar to OECD TG 402, groups of 5 New Zealand White rabbits/sex were dermally exposed to 4-methylmorpholine 4-oxide (50% aqueous solution) for 24 hours toat least 20% of the body surface area at a dose of 8000 mg/kg bw. Animals were then observed for 14 days.

There were no mortalities observed. All animals exhibited weight losses or showed no change in weight at Day 7, but all (except one female) gained weight between Days 7 and 14. However, two of the males exhibited overall weight loss at Day 14. Observations made at necropsy were similar to those seen in control animals in the laboratory or were considered to represent normal physiologic variations. After 24h, animals exhibited well-defined or moderate to severe erythema, generally with very slight or slight edema.

Based on these findings, the dermal LD50 for males and females was considered to be > 8000 mg/kg bw.

As a 50% aqueous solution is used, the LD50 for the pure NMMO is considered to be greater than 4000 mg/kg. Based on the results of this study and according to the criteria of the CLP Regulation, the substance should not be classified for acute dermal toxicity.