4-morpholinecarbaldehyde

Endpoint summary

Description of key information

The LD50 value derived from the key oral acute toxicity study on rats with N-formylmorpholine was > 7314 mg/kg bw.

The dermal LD50 was > 18400 mg/kg bw for New Zealand White rabbits.

The LC50 value was > 5.3 mg/l in male and female rats after 4 hour inhalation to liquid aerosol of the test-substance without any signs of mortality.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

only 7 days observation period

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: US

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: males: 172-270 g; females: 124-206 g
- no further data


ENVIRONMENTAL CONDITIONS
- no data

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

with Traganth

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 % v/v
- Amount of vehicle: 6.68, 8.33, 10.66 and 21.4 mL/kg bw of the 30 % test item solution
- Justification for choice of vehicle: The test substance was soluble in water


MAXIMUM DOSE VOLUME APPLIED:
- 6.68, 8.33, 10.66 and 21.4 mL/kg bw of the 30 % solution

Doses:

2285, 2875, 3657, 7314 mg/kg bw (under consideration of absolute density 1.1429 g/cm3)

No. of animals per sex per dose:

- 5 rats per sex and dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: not specified
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

no data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 7 314 mg/kg bw

Based on:

test mat.

Remarks on result:

other: reported as > 6.4 mL/kg bw

Mortality:

No deaths occured in any dose group.

Clinical signs:

other: Animals showed a slightly disturbed general condition and ruffled fur within the first days of observation. All clinical signs ceased from day 6.

Gross pathology:

No substance related abnormalities were detected after necropsy.

Interpretation of results:

GHS criteria not met

Executive summary:

Based on the results observed and by applying the evaluation criteria it was concluded that N-formylmorpholine don´t need to be classified as toxic after single oral application according to Regulation 1272/2008/EC. (BASF, 1967)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

7 314 mg/kg bw

Quality of whole database:

The study is comparable to a guideline study with acceptable restrictions.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 Jan 2016 - 26 Mar 2016

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 93973556P0
- Expiration date of the lot/batch: 08 Apr 2017


STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room termparture
- Stability under test conditions: The stability of the test substance under storage conditions over the test
period was guarenteed by the sponsol.
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: male animals approx. 8 weeks, female animals approx. 11 weeks
- Weight at study initiation: female 200,5 g; male 239,5 g
- Housing: air-conditioned rooms; TYP III polycarbonate cages; wooden gnowing blocks as
enrichment, single housing or up to 5 animals, dust-free wooden bedding
- Diet: Kliba laboratory diet, mouse/rat maintenance "GLP" 12mm pellets ad libitum
- Water: Tap water ad libitum
- Acclimation period: at least 5 days before exposure

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24°C
- Humidity: 30 - 70 %
- Air changes : 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hrs/12 hrs

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

Test-substance preparation:
The test substance was dosed unchanged.
The test substance was stirred in its container before a sample for aerosol generation was taken.
Equipment: Two-component atomizer Mod. 970 (stainless steel, Schlick) Continuous infusion pumps PHD Ultra (Harvard Apparatus, Inc., Holliston, Massachusetts, U.S.A.)
Generation technique: A liquid aerosol was generated.
The aerosol was produced by continuously pumping amounts of the test substance into the two-component atomizer. Using compressed air, the aerosol was generated with the atomizer inside the exposure system.
Nose-only inhalation system INA 20 (glass-steel construction, BASF SE, volume V 55 L): the animals were restrained in glass tubes and their snouts projected into the inhalation system.
The homogenous distribution of test substance atmosphere in this inhalation system has been verified with model aerosols.
Conditioned air:
The central air conditioning system provides cold air of about 15°C. This cold air passes through an activated charcoal filter, is adjusted to room temperature of 20 to 24°C and passes through a second particle filter (H13 (HEPA) Camfil Farr, Germany). The so generated conditioned air was used to generate inhalation atmospheres.
Compressed air:
Compressed air was produced by an oil-free compressor (HT 6, Josef Mehrer GmbH & Co KG, Germany). For this purpose, air is filtered by an inlet air strainer and introduced into the compressor. After passing through a second ultra-filter (SMF 5/3, 108 mm, Donalson), the compressed air (15 bar) is stored in a storage of 1500
or 5000 L. The compressed air is conducted to the laboratories via pipes, where the pressure is reduced to 6 bar. In the laboratory, the compressed air can be taken as required.
Exhaust air:
The exhaust air was filtered and conducted into the exhaust air of the building.
The exposure system was located inside an exhaust cabin in an air-conditioned laboratory. During exposure, the following scheduled parameters were recorded four times at about 1-hour intervals:
Supply air flow (compressed air): (from a central air-conditioning system) 1.5 m³/h
The flow was adjusted and continuously measured with a flowmeter (Yokogawa).
Exhaust air flow: 1.3 m³/h
The flow was adjusted and continuously measured with a flowmeter (Yokogawa).
The lower amount of exhaust air, which was adjusted by means of a separate exhaust air system, achieved a positive pressure inside the exposure system. This ensured that the mixture of test substance and air was not diluted with laboratory air in the breathing zones of the animals.
An air change of about 27 times per hour can be calculated by dividing the supply air flows by the volume of the inhalation system.
The animals were exposed to the inhalation atmosphere for 4 hours plus equilibration time of
the inhalation systems (t99 about 10 min).
No surveillance of the oxygen content in the inhalation system was performed. The air change was judged to be sufficient to prevent oxygen depletion by the breathing of the animals, and the concentration of the test substance used could not have a substantial influence on oxygen partial pressure.
Temperature: The temperature in the inhalation system was measured with a digital thermometer (Testo).
Relative humidity: The relative humidity in the inhalation system was measured with a dielectric probe (Testo).
Particle size analysie
EACD 50% (effective aerodynamic cutoff diameter 50%) defines the separation characteristic of each impactor stage. 50% of particles with the EACD given are deposited in the pertinent impactor stage; the remainder has reached one of the following stages.
MMAD (mass median aerodynamic diameter) is the calculated aerodynamic diameter which divides the size distribution in half when measured by mass.
Geometrical standard deviation (GSD) is the ratio of the estimated 84 percentile to the 50 percentile and indicates the slope of the cumulative particle size distribution curve.
Sample 1 MMAD (μm) 2,7 GSD 3.0
Sample 2 MMAD (µm) 3.0 GSD 3.0

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5,319 mg/l

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Feed and Water: A check for the presence of feed and drinking water was made twice a day on workdays and once daily on weekends and public holidays.
- Body weight determination: Individual body weights once during the acclimatization period, shortly before exposure (day 0) and at least on days 1, 3 and 7,
and before the sacrifice of the animals at the end of the observation period.
- Signs: Clinical observations were recorded for each animal before exposure, separately several times during exposure (usually hourly) and after exposure. At least once daily on the preexposure day and during the post exposure observation period.
- Mortality: A check for any dead or moribund animal was made twice each workday and once on Saturdays, Sundays and on public holidays.
- Pathology: At the end of the observation period the animals were sacrificed with CO2-inhalation in a chamber with increasing concentration over time, and were subjected to gross-pathological examination.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

>= 5.319 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

no mortality occurred

Clinical signs:

other: abdominal respiriation, intermittent respiration indicating local irritation effect, piloerection and substance contaminated fur

Body weight:

the mean body weights decreased on the first post exposure observation day but decreased thereafter.

Gross pathology:

no gross pathological abnormalities were detected during necropsy in the animals at the termination of the study

Interpretation of results:

GHS criteria not met

Conclusions:

Under the current study conditions, the LC50 value was > 5.3 mg/l in male and female rats after 4 hour inhalation to liquid aerosol of the test-substance.

Executive summary:

Based on the results observed and by applying the evaluation criteria it was concluded that N-formylmorpholine don´t need to be classified as toxic after single inhalation application according to Regulation 1272/2008/EC. (BASF, 2016).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 319 mg/m³ air

Quality of whole database:

It is a guideline study

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

not applicable

Principles of method if other than guideline:

Acute dermal toxicity was estimated by a technique closely akin to the one-day cuff Method of Draize and associates.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.5 - 3.5 kg
- no further data

ENVIRONMENTAL CONDITIONS
- no data

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

Acute dermal toxicity was estimated by a technique closely akin to the one-day cuff method of Draize and associates using groups of four male albino New Zealand rabbits weighing 2.5 to 3.5 kg.

The fur was removed from the entire trunk by clipping, and the dose was retained beneath an impervious plastic film. The animals were immobilized during the 24-hour contact period, after which the film was removed and the rabbits were caged for the subsequent 14-day observation period.
Based upon mortalities during a 14-day observation period, the most probable LD50 value and its fiducial range were estimated by the method of Thompson using the tables of Weil.

Duration of exposure:

24 hours

Doses:

18400 mg/kg bw (corresponding to 16 mL/kg bw under consideration of the absolute density)

No. of animals per sex per dose:

4 male animals per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- no further data

Statistics:

The most probable LD50 value and its fiducial range are estimated by the method of Thompson using the tables of Weil.

Sex:

male

Dose descriptor:

LD50

Effect level:

> 18 400 mg/kg bw

Remarks on result:

other: LD50 > 16 mL/kg bw

Mortality:

no deaths

Clinical signs:

other: no data

Gross pathology:

no data

Interpretation of results:

GHS criteria not met

Executive summary:

Based on the results observed and by applying the evaluation criteria it was concluded that N-formylmorpholine don´t need to be classified as toxic after single dermal application according to Regulation 1272/2008/EC. (Carpenter, 1974)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

18 400 mg/kg bw

Quality of whole database:

The study meets generally accepted scientific standards and is acceptable for assessment.

Additional information

After a single oral or dermal exposure N-formylmorpholine was virtually non-toxic. The inhalation of a highly saturated vapour-air-mixture represented no acute hazard.

Oral:

In the key acute oral toxicity study (BASF, 1967; XVII83), groups of male and female US rats (5/sex) were given a single oral gavage dose of the test item (30 % in water with Traganth) at doses of 2285, 2875, 3657 or 7314 mg/kg bw and observed for 7 days. No mortalities occurred during the test and no abnormalities were found at necropsy after 7 days. Thus, the oral LD50 for male and female rats in this study was determined to be > 7360 mg/kg bw.

The very low acute oral toxicity hazard of the test item was confirmed in a supporting study by Carpenter et al (1974). Groups of 5 male Wistar rats per dose level were exposed by single oral gavage administration and then observed for 14 days. The oral LD50 was determined to be 6.5 mL/kg bw which corresponds to 7475 mg/kg bw.

Inhalation:

To determine the acute inhalation toxicity (single 4-hour exposure, nose only) of N-formylmorpholine as a liquid aerosol a study was performed in male and female Wistar

rats according to OECD-Guideline method 403. The actual measured concentration was 5.319 mg/L (analytical concentration, limit test). Cascade impactor measurements resulted in particle size distributions with mass median aerodynamic diameters (MMADs) of 2.7 and 3.0 μm, which are well within the respirable range. No mortality occurred at the tested concentration. Clinical signs of toxicity comprised of abdominal respiration, intermittent respiration indicating local irritation effect. Moreover, piloerection and substance contaminated fur. These various effects were observed from hour 3 of exposure through to study day 5. No clinical signs and findings were observed from study day 6 onwards. The mean body weights of the animals decreased on the first post exposure observation day but increased thereafter. No gross pathological abnormalities were detected during the necropsy in the animals at the termination of the study. Under the current study conditions, the LC50 value was > 5.3 mg/L (calculated based on analytical concentration) in male and female Wistar rats after 4 hour inhalation exposure to liquid aerosol of N-formylmorpholine.

In an acute inhalation toxicity study (BASF, 1967; XVII83) a total of 12 rats (6/sex) were whole body exposed to the test item (saturated atmosphere at 20 °C) for 8 hours.Animals then were observed for 7 days. No mortality occured. No test item-related findings were noted at necropsy.

In a supporting study (Carpenter et al, 1974) using the same experimental design and a 14 -day observation period, 8 -hour exposure of 6 rats (sex not specified) to concentrated test item vapour similarly resulted in no mortality.

On this basis, inhalation of a concentrated vapor of the test item did not pose an acute risk to animals' health.

Dermal:

In an acute dermal toxicity study (Carpenter et al., 1974) acute systemic toxicity following dermal exposure to the test substance was estimated by a technique closely akin to the one-day cuff method of Draize and associates using four male albino New Zealand rabbits weighing 2.5 to 3.5 kg. The animals were exposed to the test item at a single dose of 16 mL/kg bw corresponding to 18400 mg/kg bw in a occlusive manner for 24 h. Based upon the lack of mortalities during the 14-day observation period, the LD50 value was considered to be greater than 18400 mg/kg bw.

I.P.:

In an acute dermal toxicity study (BASF, 1967; XVII83), groups of male and female Kissleg mice (5/sex) were given a single dose of the test item intraperitoneally (20 or 30 % in water with Traganth) at doses of 1150, 1437.5, 2875, 3680, 4600, 5750, 7360 mg/kg bw and observed for 7 days.

No deaths occurred up to a dose of 2875 mg/kg bw. At 3680 mg/kg bw 3/10 animals (2/5 males and 1/5 females) died within 7 days. At 4600 mg/kg bw 6/10 animals (2/5 males and 4/5 females) died, 5 of them within 24 hours.- At 5750 and 7360 mg/kg bw all male and female mice (10/10 each) died within 2-3 hours. No abnormalities were found at necropsy after 7 days ; in some animals adhesions in the abdominal cavity were observed. A LD50 for male and female mice after intraperitoneal administration of the test item was calculated to be 4025 mg/kg bw in this study.

Justification for selection of acute toxicity – oral endpoint
The key study was selected.

Justification for selection of acute toxicity – inhalation endpoint
The key study was selected.

Justification for selection of acute toxicity – dermal endpoint
The key study was selected.

Justification for classification or non-classification

Based on the results of the acute toxicity studies, the test item is not subjected to classification and labelling for acute toxic effects according to Regulation 1272/2008/EC.