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Description of key information

The oral LD50 value of the test item in rats is >7136 mg/kg bw (calculated by density from >6400 mm³/kg bw).
An 8h inhalation exposure of rats to an atmosphere enriched with the test item caused no deaths. The LC50 was >0.125 mg/L and was calculated from the vapour pressure of acetylmorpholine (0.022 hPa at 20°C).
The acute dermal LD50 of the initiated study is >2000 mg/kg bw.

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
Study period:
1967-03-22 to 1967-04-05
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study predating guidelines and GLP, but meeting the principles of OECD TG 401.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(Study predating Guideline)
Deviations:
not applicable
Principles of method if other than guideline:
Method: other: BASF test
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: "US-rats"
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 166 - 280 g (males); 156 - 200 g (females)

ENVIRONMENTAL CONDITIONS
- no data

IN-LIFE DATES: From: 1967-03-29 To: 1967-04-05
Route of administration:
oral: gavage
Vehicle:
other: aqueous tragacanth emulsion
Details on oral exposure:
VEHICLE
- Vehicle concentration: 30% (6400, 3200 mm3/kg bw) , 20% (1600 mm3/kg bw), 2% (200 mm3/kg bw)

MAXIMUM DOSE VOLUME APPLIED:
21, 3 mL / kg
Doses:
6400, 3200, 1600 or 200 mm3 / kg bw, corresponds to:
7136, 3568, 1784 or 223 mg / kg bw ; calculation based on density of test item
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: body weight taken at study start only for dose determination, but not reported
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs monitored but frequency unknown, gross necropsy on fatalities
Statistics:
not performed
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 7 136 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Liquid: calculation based on density
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 6.4 mL/kg bw
Based on:
test mat.
Mortality:
6400 mm3 / kg bw: 3/10 (1/10 within 24 h, 2/10 within 48 h)
3200 mm3 / kg bw: 0/10
1600 mm3 / kg bw: 1/10 (between day 2 and day 7)
200 mm3 / kg bw: 0/10
Clinical signs:
3200 and 6400 mm3 / kg bw: Laboured breathing, hunched posture, ptosis, red crust around eyes and snout, mild apathy, ruffled fur (on day of dosing, surviving animals recuperated)
Body weight:
No data reported
Gross pathology:
Chronic bronchitis and brochiectasis (10x, non test item related)
Perished animals: bloated stomach (2x), bloated gut (1x), pallid liver (1x)
Other findings:
None
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

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Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1967-03-22 to 1967-04-05
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study predating guidelines and GLP, but performed close to OECD TG 403.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
not applicable
Principles of method if other than guideline:
Based on H.F. Smyth et al.: Am. Ind. Hyg. Ass. J. 23, 95-107 (1962)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Two group weights at study initiation: 1280 g (28.03., 3 males / 3 females); 1325 g (29.03., 3 males / 3 females)

ENVIRONMENTAL CONDITIONS
- no data

IN-LIFE DATES: From: 1967-03-29 To: 1967-04-05
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: not specified
- Exposure chamber volume: not specified
- Method of holding animals in test chamber: not specified
- Source and rate of air: not specified
- System of generating vapour: bubbling 200 L/h air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder for 8 hours
- Temperature, humidity, pressure in air chamber: at 20°C, nothing else specified

TEST ATMOSPHERE
- Brief description of analytical method used: no analytical method used
- Samples taken from breathing zone: no

TEST ATMOSPHERE
- Particle size distribution: not applicable (vapour)
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
8 h
Concentrations:
Calculation from vapour pressure of test item:

Concentration = VP / TP * 1000000 * MW / MVo
= 0.022 / 1013 * 1000000 * 129.16 /22.414 = 125 mg/m³ or 0.125 mg/L air
Where:
- Vapour pressure (VP): 0.022 hPa
- Total pressure (TP): 1013 mm Hg
- Molecular weight (MW): 129.16
- MolVolume (MVo): 22.414


Nominal concentrations from raw data:
Group 1a.: 0.1685 g/L (269.54 g test item / 1600 L air)
Group 1b.: 0.1700 g/L (271.93 g test item / 1600 L air)
Group 2a.: 0.1374 g/L (219.87 g test item / 1600 L air)
Group 2b.: 0.1388 g/L (222.06 g test item / 1600 L air)

No. of animals per sex per dose:
12 males, 12 females
Control animals:
no
Details on study design:
two groups (6 males, 6 females each) exposed for 8h each
Group 1: 28. 3.1967
Group 2: 29. 3.1967
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: body weight taken at study start and end
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (groupwise)
Statistics:
not performed
Preliminary study:
Considering the relatively low vapour pressure of 0.022 mg Hg at 20°C, the calculated test item concentration of 170 mg/L air was implausibly high. The saturated atmospere calculated from the vapour pressure is 1.7 mg/L.
Sex:
male/female
Dose descriptor:
LC0
Effect level:
> 0.125 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
8 h
Remarks on result:
other: Calculated from vapour pressure (0.027 hPa at 20°C)
Mortality:
No mortality occurred
Clinical signs:
other: None
Body weight:
Both groups gained body weight between day 1 and day 7:
Total group 1, day 1: 1280 g; day 7: 1415 g
Total group 2, day 1: 1325 g; day 7: 1433 g
Gross pathology:
chronic bronchitis (1x)
Other findings:
None
No mortalities after 8-hour exposure to an atmosphere enriched with the substance at 20°C.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
125 mg/m³

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
Study period:
2012-02-16 to 2012-04-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study according to OECD TG 402.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japan MAFF 8147
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: male animals approx. 8 weeks, female animals approx. 12 weeks
- Weight at study initiation: m= mean 229.0 g, f = 207.8 g
- Fasting period before study:
- Housing: single
- Diet: VRF1(P); SDS Special Diets Services, 67122 Altrip, Germany
- Water: ad libitum
- Acclimation period: at least 5 days before the beginning of the experimental phase

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3 oC
- Humidity: 30-70 %
- Air changes: approx. 10 per hr
- Photoperiod (hrs dark / hrs light): 12 h / 12 h (6.00 a.m. – 6.00 p.m. / 6.00 p.m. – 6.00 a.m.)

IN-LIFE DATES: From: 2012-02-16 To: 2012-03-27
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: about 40 cm2 (corresponds to at least 10% of the body surface)
- Type of wrap if used: The test item was covered with an air-permeable dressing (4 layers of absorbent gauze (Ph. Eur. supplied by Lohmann GmbH & Co., KG) and stretch bandage (Fixomull® Stretch (adhesive fleece) supplied by Beiersdorf AG).

REMOVAL OF TEST SUBSTANCE
- Washing: yes, with warm water
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount applied: 1.8 mL/kg bw
- Constant volume or concentration used: yes
Duration of exposure:
24h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of clinical observations: Recording several times on the day of administration, and at least once daily thereafter each workday for the individual animals.
- Scoring of skin findings: Individual readings 30 – 60 minutes after removal of the semi-occlusive dressing (day 1), weekly thereafter and on the last day of observation.
- Frequency of weighing: Individual body weights shortly before administration (day 0), weekly thereafter and on the last day of observation.
- Necropsy of survivors performed: Yes, gross-pathology examination on the last day of the observation period after sacrifice.
- Mortality: A check for any dead or moribund animals was made at least once each workday.
Statistics:
no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
No systemic clinical signs were observed during clinical examination. No local effects were observed.
Body weight:
The mean body weight of the male animals increased within the normal range throughout the study period.

The mean body weight of the female animals did not adequately change during the first post-exposure observation week, probably due to the bandage procedure, but increased during the second week within the normal range.
Gross pathology:
No abnormalities were detected during necropsy of all animals.
Other findings:
None
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

In an acute oral toxicity study (BASF AG, 1967), rats (5/sex) were given a single oral dose of test item in aqueous tragacanth emulsion at doses of 6400, 3200, 1600 or 200 mm³ / kg bw. Animals were then observed for 7 days. Oral LD50 combined: >6400 mm³/kg bw (calculated: >7136 mg/kg bw); no differences occurred between the sexes. Mortality at the highest dose was too low to determine the LD50.The following treatment related clinical signs were noted: laboured breathing, hunched posture, ptosis, red crusts around eyes and snout, mild apathy, ruffled fur.

In an acute inhalation toxicity study (BASF AG, 1967), groups of young adult rats (5/sex) were exposed by inhalation route to an enriched atmosphere of N-acetylmorpholin for 8 hours to the whole body at nominal concentrations of 170 mg/L at maximum. Animals then were observed for 7 days. During this assay, neither clinical signs nor body weight development was impaired and no mortality occurred. Nominal LC50 (combined) from raw data: = > 170   mg/L. However, considering the relatively low vapour pressure of 0.022 mg Hg at 20°C, the calculated test item concentration of 170 mg/L air is implausibly high. Saturation of the atmospere, calculated from the vapour pressure, is reached at 0.125 mg/L. Thus the calculated LC50 was determined at >0.125 mg/L.

In an acute dermal toxicity study (Bioassay, 2012), rats (5/sex) were given a single dermal dose of the undiluted test item of 2000 mg/kg bw. Animals were then observed for 14 days. No death occurred, and no clinical signs, systemically and locally, were observed. Body weight development was unaffected and no macroscopic pathologic abnormalities were noted. Thus the acute dermal LD50 was >2000 mg/kg bw.



Justification for selection of acute toxicity – oral endpoint
most reliable study

Justification for selection of acute toxicity – inhalation endpoint
most reliable study

Justification for selection of acute toxicity – dermal endpoint
most reliable study

Justification for classification or non-classification

Based on the available data, the test item is not subject to C&L according to Directive 67/548/EEC or Regulation 1272/2008/EC.