4-methylmorpholine

Endpoint summary

Description of key information

Acute toxicity - oral: A K1 acute oral toxicity test was performed in male and female Sprague Dawley rats according to a guideline similar to OECD Guideline 401 (Mallory VT, 1990). This study was selected as key study.  

Acute toxicity - dermal: A K1 acute dermal toxicity test was performed in male and female New Zealand White rabbits according to a guideline similar to OECD Guideline 402 (Mallory VT, 1990). This study was selected as key study.

Acute toxicity - inhalation: In a supporting study, BASF (1964) performed an acute inhalation toxicity study equivalent to OECD Guideline 403. Following mortalities were observed: 6/6 rats died when exposed to the saturated vapour of the test substance for 1 hour, 5/6 rats died when exposed to the saturated vapour of the test substance for 30 min and all 12 rats survived when exposed to the saturated vapour of the test substance for 10 min. No LC50 value could be determined. No acute inhalation study is to be performed as the substance is classified as corrosive to the skin.

Acute toxicity - other routes: In an acute toxicity study via the intraperitoneal route (single exposure), no animal died in the 184, 368 and 735 mg/kg bw dose groups, 1/10 in the 919 mg/kg bw dose group, 9/10 in the 1149 mg/kg bw dose group and 5/5 in the 1471 mg/kg bw dose group. The LD50 was determined to be situated in the range > 919 - < 1149 mg/kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

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

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

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)

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

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.

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

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

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.

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.

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.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable report similar to guideline study (no GLP, TS purity not specified; limited documentation, 7-day observation period, body weight determined only at study start)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

limited documentation, 7-day observation period, body weight determined only at study start

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-methyl-morpholin

Species:

rat

Strain:

other: Heigl-rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: males: 158-234 g, females: 108-200 g

ENVIRONMENTAL CONDITIONS
no data

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2 %, 8 %, 10% or 20 %
- Amount of vehicle (if gavage): 5-32 ml/kg

MAXIMUM DOSE VOLUME APPLIED:
32 ml/kg

Doses:

ca. 184, 368, 735, 1471, 2941 and 5883 mg/kg bw (original values: ca. 0.2, 0.4, 0.8, 1.6, 3.2 and 6.4 ml, respectively from the low to the high dose levels, calculated assuming TS density of 0.9192 g/cm3)

No. of animals per sex per dose:

5 or 10 (only 1471 and 2941 mg/kg bw)

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: observations were made, frequency not specified, rats were weighed on the day of dosing
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, gross pathology

Statistics:

no data

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 471 - < 2 941 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no animal died in the 184, 368 and 735 mg/kg bw dose groups, 8/20 in the 1471 mg/kg bw dose group, 13/20 in the 2941 mg/kg bw dose group and 10/10 in the 5883 mg/kg bw dose group.

Mortality:

see above

Clinical signs:

other: high dose animals: convulsions directly after application, later apathy, dyspnoea, and once in a while convulsions, most animals died in 1-2 hours or over night lower dose animals: apathy, face-down position and dyspnoea on the day of dosing, on the later

Gross pathology:

sacrificed animals after 7 days: organs without findings
dead animals: haemorrhagic lungs and haemorrhagic enteritis

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral LD50 in male and female rats was observed to be within the range > 1471 - < 2941 mg/kg bw. The substance is considered to be classified as acute oral toxicant category 4 according to the criteria laid down in the CLP Regulation.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1978-08 - 1978-10

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Well documented non-GLP study performed using a method similar to OECD401 with minor deviations.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

some data lacking on test substance and animals used

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): RC-106 or RC-107
- Substance type: clear liquid
- Physical state: liquid
- Analytical purity: no data
- Lot/batch No.: no data
- Stability under test conditions: no data
- Storage condition of test material: no data

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Murphy Breeding Laboratories, Inc.
- Age at study initiation: no data
- Weight at study initiation: 211-288 g (males); 157-202 g (females)
- Fasting period before study: 24h
- Housing: in groups in stainless steel wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: the samples were administered undiluted. Maximum dose was 10 ml/kg bw.

Doses:

0.464, 1.00, 2.15, 4.64, 10.0 ml/kg bw

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: all animals were observed closely for gross signs of systemic toxicity and mortality at frequent intervals during the day of dosage and at least once daily thereafter. Body weights only recorded on day 0 and day 14.
- Necropsy of survivors performed: yes

Statistics:

Moving average method for mortality data (Horn HJ, 1956, Biometrics 12: 311-322)

Sex:

male

Dose descriptor:

LD50

Effect level:

1.71 mL/kg bw

Based on:

test mat.

Remarks:

RC-106

95% CL:

>= 1.26 - <= 2.33

Sex:

female

Dose descriptor:

LD50

Effect level:

2 mL/kg bw

Based on:

test mat.

Remarks:

RC-106

95% CL:

>= 1.23 - <= 3.24

Sex:

male

Dose descriptor:

LD50

Effect level:

1.96 mL/kg bw

Based on:

test mat.

Remarks:

RC-107

95% CL:

>= 1.22 - <= 3.14

Sex:

female

Dose descriptor:

LD50

Effect level:

1.26 mL/kg bw

Based on:

test mat.

Remarks:

RC-107

95% CL:

>= 0.926 - <= 1.71

Mortality:

Male rats given RC-106: 0/5 died at 0.464 ml/kg and 1.0 ml/kg; 4/5 died at 2.15 ml/kg; 5/5 died at 4.64 and 10.0 ml/kg
Female rats given RC-106: 0/5 died at 0.464 ml/kg; 1/5 died at 1.0 ml/kg; 2/5 died at 2.15 ml/kg; 5/5 died at 4.64 and 10.0 ml/kg
Male rats given RC-107: 1/5 died at 0.464 ml/kg; 0/5 died at 1.0 ml/kg; 3/5 died at 2.15 ml/kg; 5/5 died at 4.64 and 10.0 ml/kg
Female rats given RC-107: 0/5 died at 0.464 ml/kg; 1/5 died at 1.0 ml/kg; 5/5 died at 2.15, 4.64 and 10.0 ml/kg

Clinical signs:

other: Depression, labored breathing, piloerection, depressed reflexes

Gross pathology:

No gross pathological alterations.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Male and female LD50 values ranged from 1573 - 1800 mg/kg bw and from 1159 - 1840 mg/kg bw, respectively, taking into account a relative density of 0.92.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

No data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Original reference not available.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

GLP compliance:

no

Test type:

standard acute method

Specific details on test material used for the study:

- Name of test material (as cited in study report): N-methylmorpholine

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: unspecified

Vehicle:

not specified

Doses:

No data

No. of animals per sex per dose:

No data

Control animals:

not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

2 700 mg/kg bw

Based on:

test mat.

Mortality:

No data

Clinical signs:

other: No data

Gross pathology:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

The single oral dose LD50 for rats is approximately 2700 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 442.3 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Acceptable report similar to guideline study (IHT; no GLP, TS purity not specified; animals were observed for only 7 days, limited documentation, exposure period of up to 1 hour, concentration of test substance in air mixture was not verified analytically; mortality occurred after 30 min/1 hour exposure).

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

(adopted on 1981, 12th May; inhalation hazard test)

Deviations:

yes

Remarks:

animals were observed for only 7 days, limited documentation, exposure period of up to 1 hour, concentration of test substance in air mixture was not verified analytically

GLP compliance:

no

Test type:

other: inhalation hazard test

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-Methyl-morpholin

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
no data

ENVIRONMENTAL CONDITIONS
no data

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

clean air

Details on inhalation exposure:

The test demonstrates the toxicity of an atmosphere saturated with vapors of the volatile components of a test substance at 20 °C.
Young adult laboratory rats, 3 or 6 per sex, were exposed sequentially to the vapors generated by bubbling 200 L/h air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder for 10 or 30 min and 1 hour.

Analytical verification of test atmosphere concentrations:

no

Remarks:

No analytical determination of the atmosphere concentrations was performed. The nominal concentration was calculated as quotient of the amount of test substance weight loss during exposure, and the amount of air used during exposure.

Duration of exposure:

ca. 10 - ca. 60 min

Remarks on duration:

10 and 30 minutes as well as 1 hour

Concentrations:

119.5-130.2 mg/l

No. of animals per sex per dose:

3-6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: all rats of a exposure group were weighed before the study and after the 7 days of exposure (survivers), observations were performed, frequency not stated
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, gross pathology

Statistics:

no data

Key result

Sex:

male/female

Dose descriptor:

other: IHT

Effect level:

ca. 119.5 - ca. 130.2 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

1 h

Remarks on result:

other: All 12 rats survived an exposure to the saturated vapour for 10 minutes. Exposure for 30 min and 1 hour led to death (5/6 and 6/6 animals died respectively).

Mortality:

6/6 rats died when exposed to the saturated vapour of the test substance for 1 hour.
5/6 rats died when exposed to the saturated vapour of the test substance for 30 min.
All 12 rats survived when exposed to the saturated vapour of the test substance for 10 min.

Clinical signs:

other: 1 hours exposure: vigorous attempts to escape, intense secretion from eyes and nose, dyspnoea, all animals died during the exposure. 30 min exposure: vigorous attempts to escape, intense secretion from eyes and nose, dyspnoea, after some time bloody secre

Body weight:

No data

Gross pathology:

Blood in the lung and the nose was observed in 3 rats of the 30 min exposure group, no other findings were noted in the other groups, organs were without findings.

Interpretation of results:

study cannot be used for classification

Remarks:

inconclusive as no LC50 value could be determined in this study

Conclusions:

In this acute inhalation toxicity test, following mortalities were observed: 6/6 rats died when exposed to the saturated vapour of the test substance for 1 hour, 5/6 rats died when exposed to the saturated vapour of the test substance for 30 min and all 12 rats survived when exposed to the saturated vapour of the test substance for 10 min. The study is considered inconclusive as no LC50 value could be determined in this study.

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-10-10 - 1990-10-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 6398-24-20, Project #90-005
- Substance type: clear, colorless liquid
- Physical state: liquid
- Stability under test conditions: There was no apparent change in the physical characteristics of the test article during administration.
- Other: specific gravity: 0.92 g/mL; pH 10.8 (taken from MSDS)

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hare-Marland, Hewitt, New Jersey, USA
- Age at study initiation: young adult animals
- Weight at study initiation: males 2224-2691 g (mean 2430 g); females 2224-2775 g (mean 2380.6 g)
- Housing: Rabbits were housed individually in 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): Purina Rabbit Ration, H.F., ad libitum, checked daily and added or replaced as needed. Feeders are designed to reduce soiling, bridging and scattering
- Water (e.g. ad libitum): fresh tap water, ad libitum
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 3°C
- Humidity (%): 30 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
Approximately 24 hours before testing, fur was clipped from the dorsal area of the trunk of the test animals. The test article was applied directly onto the exposed intact skin of the animals taking care to spread the substance evenly over the entire area. A square gauze patch was placed on the animals to cover the dosed area. A square gauze patch was placed on the animals to cover the dosed area. The animals were wrapped with rubber dam and an elastic bandage to retard evaporation.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test article was held in contact with the skin for twenty-four hours. Following the twenty-four hour period of exposure, the wrappings were removed.

Duration of exposure:

24 hours

Doses:

3000 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 were recorded daily through day 14. Body weights were recorded at initation and on days 7 and 14 or upon death. All surviving rabbits were sacrificed by a lethal injection of BeuthanasiaR solution on day 14 and a gross necropsy was performed.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 000 mg/kg bw

Based on:

test mat.

Mortality:

Three of ten rabbits died during the study (2 males, 1 female).

Clinical signs:

other: Clinical signs observed during the limit test included decreased activity, decreased muscle tone, abnormal stance, abnormal gait, hind end drop and dyspnea.

Gross pathology:

Necropsy of the animals dying on study included pale and/or mottled liver, pale and/or mottled kidneys, dark red and mottled lungs, oral and/or nasal discharge, and severe irritation of the underlying muscle at the application site.

Interpretation of results:

GHS criteria not met

Conclusions:

Based upon the observations made in this Acute Exposure Dermal Toxicity Study in rabbits, the estimated dermal LD50 for the substance was determined to be greater than 3000 mg/kg. The substance is considered not classified as acute dermal toxicant according to criteria laid down in the CLP Regulation.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

No data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Original reference not available.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

not specified

GLP compliance:

no

Test type:

standard acute method

Specific details on test material used for the study:

- Name of test material (as cited in study report): N-methylmorpholine

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 hours

Doses:

1.4 mL/kg

No. of animals per sex per dose:

No data

Control animals:

not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1.4 mL/kg bw

Based on:

test mat.

Mortality:

No data

Clinical signs:

other: No data

Gross pathology:

No data

Interpretation of results:

study cannot be used for classification

Conclusions:

Undiluted N-methylmorpholine appears to penetrate skin readily, since the LD50 by single, 24-hour skin contact to rabbits is about 1.4 mL/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 000 mg/kg bw

Additional information

Acute toxicity: oral

Mallory VT (1990) investigated the acute oral toxicity via gavage of 200, 400, 500, 1000, 1500 and 2000 mg/kg bw the test substance in male/female Sprague-Dawley rats (5 animals per sex and per dose). After 14 days of observation, 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. The acute oral LD50 value was observed to be 1442.3 mg/kg bw. Clinical signs included decreased activity, piloerection, salivation, abnormal gait, abnormal stance, ptosis, chromodacryorrhea, dyspnea and convulsions. 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. This study is designated as key study.

In addition, one supporting K2 study reported male and female LD50 ranges of 1573 - 1800 mg/kg bw and 1159 - 1840 mg/kg bw, respectively, taking into account a relative density of 0.92 (Matthews, 1978) and another supporting K2 study reported an acute oral LD50 in male and female rats within the range > 1471 - < 2941 mg/kg bw (BASF, 1964).

 

Acute toxicity: inhalation

No acute inhalation toxicity study needs to be conducted as the substance is classified as corrosive to the skin.

In a supporting study, BASF (1964) investigated acute inhalation toxicity of the test substance in 6 male/female rats. The test demonstrates the toxicity of an atmosphere saturated with vapors of the volatile components of a test substance at 20 °C. Young adult laboratory rats, 3 or 6 per sex, were exposed sequentially to the vapors (119.5 - 130.2 mg/L) generated by bubbling 200 L/h air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder for 10 or 30 min and 1 hour. In this acute inhalation toxicity test, following mortalities were observed: 6/6 rats died when exposed to the saturated vapour of the test substance for 1 hour, 5/6 rats died when exposed to the saturated vapour of the test substance for 30 min and all 12 rats survived when exposed to the saturated vapour of the test substance for 10 min.

 

Acute toxicity: dermal

Mallory VT (1990) investigated acute dermal toxicity of the test substance in New Zealand White male/female rabbits (5 animals per sex and per dose) after 24 hours of exposure to 3000 mg/kg bw. After 14 days of observation, an LD50 value of > 3000 mg/kg bw was reported. Three of ten rabbits died during the study (2 males, 1 female). Clinical signs observed during the limit test included decreased activity, decreased muscle tone, abnormal stance, abnormal gait, hind end drop and dyspnea. Necropsy of the animals dying on study included pale and/or mottled liver, pale and/or mottled kidneys, dark red and mottled lungs, oral and/or nasal discharge, and severe irritation of the underlying muscle at the application site. This study is designated as key study.

 

Acute toxicity: other routes:

In an acute toxicity study via the intraperitoneal route (single exposure), no animal died in the 184, 368 and 735 mg/kg bw dose groups, 1/10 in the 919 mg/kg bw dose group, 9/10 in the 1149 mg/kg bw dose group and 5/5 in the 1471 mg/kg bw dose group. The LD50 was determined to be situated in the range > 919- < 1149 mg/kg.

Justification for classification or non-classification

Based on the available data and according to the CLP criteria, the substance is classified for acute oral toxicity category 4 (H302).

Based on the available data and according to the CLP criteria, the test substance should not be classified for acute dermal toxicity.

The available data for the inhalation route cannot be used for derivation of the classification as based on the study results no LC50 value could be derived. No key study is available to conclude on the classification.