Registration Dossier

Administrative data

Description of key information

Acute toxicity oral: BASF AG, 1972: comparable to OECD TG 401, rats, 1504, 1880, 2350, 3008, and 3760 and 6016 mg/kg bw/day. LD50 = 3010 mg/kg bw.

Acute toxicity dermal: TSCATS: OTS 0516779; comparable to OECD TG 402, rats, limit test. LD50 > 3160 mg/kg bw.  

Acute toxicity inhalation: BASF AG, 1979: comparable to OECD TG 403, 2.23, 4.92, 5.10, 5.85 mg/L. LC50 > 5.85 mg/L equal, 5850 mg/m³

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:
not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented report which meets basic scientific principles.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
- Principle of test: BASF internal method (in principle comparable to OECD Guideline 401).
- Short description of test conditions: 5 animals/sex were treated by single gavage application with an aqueous solution of DMF.
- Parameters analysed / observed: The animals were observed for mortality and for clinical symptoms of toxicity for 7 days. Surviving animals were sacrificed for the purpose of necropsy; as well as the animals that died during the observations period.
GLP compliance:
no
Test type:
other: comparable with OECD 401
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Zentralinstitut für Versuchstierzucht Hannover
- Weight at study initiation: male: 153 g (mean), female: 135 g (mean)
- Diet: Wayne-Lab-Blox, Allied Mills, Chicago, ad libitum
- Water: water ad libitum
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
no details
Doses:
6400, 4000, 3200, 2500, 2000, 1600 mL/kg bw (6016, 3760, 3008, 2350, 1880, 1504 mg/kg bw - conversation in mg/kg is based on the density: d = 0.94 g/cm3).
No. of animals per sex per dose:
6016 mg/kg: 3 females and 2 males
3760, 3008, 2350, 1880, 1504 mg/kg: 5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 010 mg/kg bw
95% CL:
2 480 - 3 650
Remarks on result:
other: conversion in mg/kg is based on the density: d= 0.94 g/cm³.
Mortality:
6016 mg/kg: 1 female died within 48 h and all animals died within 7 days.
3760 mg/kg: 1 female died within 48 h and 1 male and 4 female died within 7 days.
3008 mg/kg: 3 males and 3 females died within 7 days.
1880 mg/kg: 1 male and 1 female died within 7 days.
1504 mg/kg: 1 male died within 7 days.
Clinical signs:
6016 mg/kg: 24 h post application staggering, piloerection, paresis of fore limbs was noted.
3760, 3008, 2350 mg/kg: piloerection, slight apathy.
1880 mg/kg: 4 days post application slight staggering, piloerection.
1504 mg/kg: piloerection, slight apathy.
Body weight:
no data.
Gross pathology:
6016 mg/kg: 2x decomposition, 1x hydrothorax and lung filled with liquid. Pale liver, kidney and spleen with autolytic alterations.
3760 mg/kg: 1x lung filled with blood. Pale liver with distinct pattern on lobule.
3008 mg/kg: distinct pattern on liver lobule.
1880 mg/kg: 1x hydrothorax, 2x pattern on liver lobule, kidney and spleen decomposed.
Other findings:
- Histopathology: 1x desquamative pneumonia

Mortality:

 Dose (mg/kg)  Gender  Conc.(%)  dead within 1 h  dead within 24 h  dead within 48 h  dead within 7 days
6016  male 50 0/2 0/2 0/2 2/2
6016  female 50 0/3 0/3 1/3 3/3
3760  male 25 0/5 0/5 0/5 1/5
3760  female 25 0/5 0/5 1/5 4/5
3008  male 25 0/5 0/5 0/5 3/5
3008  female 25 0/5 0/5 0/5 3/5
2350  male 25 0/5 0/5 0/5 0/5
2350  female 25 0/5 0/5 0/5 0/5
1880  male 25 0/5 0/5 0/5 1/5
1880  female 25 0/5 0/5 0/5 1/5
1504  male 25 0/5 0/5 0/5 1/5
1504  female 25 0/5 0/5 0/5 0/5

May be harmful if swallowed.

Interpretation of results:
other:
Remarks:
EU GHS criteria not met
Conclusions:
Main symptoms observed were apathy and staggering after oral intake.
The LD50 for both sexes was determined to be 3010 mg/kg bw/day.
Executive summary:

Study design

This non GLP-study was performed similar to the OECD Test Guideline 401: Acute Oral Toxicity, following a BASF internal method.

In the study DMF was administered once by gavage as aqueous solution in concentrations of 25 % (doses from 1504 mg/kg to 3760 mg/kg bw day) and 50 % (at dose of 6016 mg/kg bw/day), respectively, to 10 Sprague-Dawely rats per group at the dose levels of 1504, 1880, 2350, 3008, and 3760 mg/kg/ bw/day and to 5 rats per group at 6016 mg/kg bw/day. Mortality and signs of toxicity were recorded 1, 24 and 48 hours and 7 days after the substance administration. Animals that died and the surviving animals were sacrificed and necropsied after the 7 -day post observation period.

Results

48 hours after substance application one animal each at both highest dose levels (6016 and 3760 mg/kg bw/day) died. After 7 days all animals died at 6016 mg/kg bw/day, 5 of 10 rats died at 3760 mg/kg bw/day and 6 of 10 rats at 3008 mg/kg bw/day. There were no dead animals at 2350 mg/kg bw/day and 2 of 10 and 1of 10 rats were dead after 7 days at 1880 and at 1504 mg/kg bw/day, respectively. At necropsy all animals that died and those sacrificed at the end of the study, discoloured livers were seen. In relation to the dose administered the main symptoms observed were apathy and staggering.

Conclusion

Main symptoms observed were apathy and staggering after oral intake. The LD50 for both sexes was determined to be 3010 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 010 mg/kg bw

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented report which meets basic scientific principles.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
no
Test type:
other: comparable with OECD 403 guideline
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: WIGA, Sulzfeld and MUS RATTUS, Brunnthal, Germany
- Weight at study initiation: male: 183 g (mean), female: 182 g (mean)
- Diet: Herilan MRH, ad libitum
- Water: tap water ad libitum
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
data not available
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gaschromatography
Duration of exposure:
4 h
Concentrations:
5.85, 5.10, 4.92, 2.23 mg/L
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: day 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
no information given
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.85 mg/L air
Exp. duration:
4 h
Mortality:
5.85 mg/L: 3 males died within 3 days post exposure.
4.92 mg/L: 2 males and 1 female died within 3 days post exposure
Clinical signs:
other:
Body weight:
No significant alterations compared to controls were observed.
Gross pathology:
Animals that died:
Heart: acute dilation and congestive hyperaemia,
Lungs: filled with blood,
Thymus: widespread haemorrhage,
Stomach: haemorrhage,
Liver: dark red/brownish; grey/brownish marbled (haemorrhagic dystrophy);
Kidneys: pale cortex, yellowish papilla.
Pancreas: punctate haemorrhages.
Other findings:
no

Mortality:

 Dose (mg/L)  male  female
 5.85  3/10  0/10
 5.10  0/10  0/10
 4.92  2/10  1/10
 2.23  0/10  0/10

Animal supplier:

5.85, 4.92, 2.23 mg/L: WIGA;

5.10 mg/L: MUS RATTUS

Weight:

 Dose (mg/L)  day 0     day 7     day 14   
   male  female  male  female  male  female
 5.85  180  179  217  204 252  219
 5.10  183  179  214  190  266  208
 4.92  187  187 205   194  267  206
 2.23  188  186  211  192  257  208
 control  178  180  219  190  254  210
Toxic/Harmful if inhaled.
Interpretation of results:
other:
Remarks:
EU GHS Criteria not met
Conclusions:
N,N-dimethylformamide is considered to be of low acute toxicity. Irregular or intermittent respiration were observed in the treated animals.
Executive summary:

Study design

This non-GLP study was performed similar to the OECD Test Guideline 403: Acute Inhalation Toxicity.

In the study 10 male and 10 female Sprague-Dawley rats per dose group were exposed by whole-body exposure to N,N-dimethylformamide (DMF) vapour for 4 hours at (analytical determined) concentrations of 2.23, 4.92, 5.10 and 5.85 mg/L. The concentration of 5.85 mL was the maximum technical attainable concentration. A concurrent control group of ten male and female animals run in parallel. After the 4-h DMF exposure, the animals were examined for 14 days. Body weight was determined before the beginning of the study, after 7 days during the study and at the end of the post observation period. The animals were daily observed for clinical signs and mortality. Animals that died during the study and the surviving animals sacrificed at the end of the post observation period were necropsied and macroscopically examined.

Results

At the analytical concentration of 2.23 mg/L all animals survived and did not show any clinical signs related to DMF exposure. In the other three treatment groups dyspnoea (irregular or intermittent respiration) and rough fur were observed as well in 3 females at 5.1 mg/L a minimal alopecia at the head. Deaths occurred 3 days after the start of the study: at 4.92 mg/L 2 of 10 males and 1 of 10 females died, at 5.1 mg/L all animals survived and at 5.85 mg/L 3 of 10 males and no female animal died.

Surviving animals recovered 6 -7 days after exposure. These animals did not show any gross lesions at necropsy, whereas the animals that died during the study had some organ findings, e.g. discoloration of the liver, haemorrhage in thymus and punctate haemorrhage in pancreas and in the gastric mucous membrane.

Conclusion

DMF is considered to be of low acute toxicity. Irregular or intermittent respiration were observed in the treated animals. LD50for both sexes was determined to be >5.85 mg/L air.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
5 850 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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
2 animals/sex were used instead of 5.
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
no data
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: the test material was applied to abraded skin of animals.
Duration of exposure:
24 hours
Doses:
3160 mg/kg bw
No. of animals per sex per dose:
2
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Day 2, 4, 8, 11 and 15 observation of exposure sites and scoring; 2 and 4 hours post-dosing and daily thereafter observation for mortality and toxic effects
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, mortality, exposure sites (scored for erythema and edema)
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3 160 mg/kg bw
Based on:
test mat.
Mortality:
1 male animal died on day 4 of the study.
Clinical signs:
No substance-related clinical findings were reported.
Gross pathology:
Gross necropsy revealed no substance-related effect.
Other findings:
No signs of systemic toxicity or percutaneous absorption were observed.
Interpretation of results:
other:
Remarks:
EU GHS criteria not met
Conclusions:
No substance-related findings were reported in the study.
LD50for both sexes is higher than 3160 mg/kg bw/day.
Executive summary:

Study design

This non-GLP study was performed according to OECD TG No. 402 Acute Dermal Toxicity. In the study, 2 male and 2 female Sprague-Dawley rats were treated with the undiluted test substance at a dose level of 3160 mg/kg under occlusive conditions on abraded skin for 24h. On days 2, 4, 8, 11 and 15 exposure sites were examined and scored for erythema and edema on a graded scale of 0 to 4.
Each animal was observed for mortality and toxic effects 2 and 4 hours post-dosing and daily thereafter.

Results

In the 14 -days post-observation period, 1/4 animals died (one male animal) on day 4 of the study, however, gross necropsy revealed no substance related effect. Among the remaining animals, no signs of systemic toxicity or percutaneous absorption were observed.

Conclusion

No substance-related findings were reported in the study. LD50for both sexes is higher than 3160 mg/kg bw/day.


Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
3 160 mg/kg bw

Additional information

Acute toxicity oral

A non-GLP study was performed similar to the OECD TG 401: Acute Oral Toxicity, following a BASF internal method.

In the study DMF was administered once by gavage as aqueous solution in concentrations of 25 % (doses from 1504 mg/kg to 3760 mg/kg bw day) and 50 % (at dose of 6016 mg/kg bw/day), respectively, to 10 Sprague-Dawely rats per group at the dose levels of 1504, 1880, 2350, 3008, and 3760 mg/kg/ bw/day and to 5 rats per group at 6016 mg/kg bw/day. Mortality and signs of toxicity were recorded 1, 24 and 48 hours and 7 days after the substance administration. Animals that died and the surviving animals were sacrificed and necropsied after the 7 -day post observation period.

48 hours after substance application one animal each at both highest dose levels (6016 and 3760 mg/kg bw/day) died. After 7 days all animals died at 6016 mg/kg bw/day, 5 of 10 rats died at 3760 mg/kg bw/day and 6 of 10 rats at 3008 mg/kg bw/day. There were no dead animals at 2350 mg/kg bw/day and 2 of 10 and 1of 10 rats were dead after 7 days at 1880 and at 1504 mg/kg bw/day, respectively.

At necropsy all animals that died and those sacrificed at the end of the study, discoloured livers were seen. In relation to the dose administered the main symptoms observed were apathy and staggering.

Main symptoms observed were apathy and staggering after oral intake. The LD50for both sexes was determined to be 3010 mg/kg bw/day.

Acute toxicity dermal

A non-GLP study was performed according to OECD TG 402 Acute Dermal Toxicity. In the study, 2 male and 2 female Sprague-Dawley rats were treated with the undiluted test substance at a dose level of 3160 mg/kg under occlusive conditions on abraded skin for 24h. On days 2, 4, 8, 11 and 15 exposure sites were examined and scored for erythema and edema on a graded scale of 0 to 4.
Each animal was observed for mortality and toxic effects 2 and 4 hours post-dosing and daily thereafter.

In the 14 -days post-observation period, 1/4 animals died (one male animal) on day 4 of the study, however, gross necropsy revealed no substance related effect. Among the remaining animals, no signs of systemic toxicity or percutaneous absorption were observed.

No substance-related findings were reported in the study. LD50 for both sexes is higher than 3160 mg/kg bw/day.

Acute toxicity inhalation

A non-GLP study was performed similar to the OECD Test Guideline 403: Acute Inhalation Toxicity.

In the study 10 male and 10 female Sprague-Dawley rats per dose group were exposed by whole-body exposure to N,N-dimethylformamide (DMF) vapour for 4 hours at (analytical determined) concentrations of 2.23, 4.92, 5.10 and 5.85 mg/L. The concentration of 5.85 mL was the maximum technical attainable concentration. A concurrent control group of ten male and female animals run in parallel. After the 4-h DMF exposure, the animals were examined for 14 days. Body weight was determined before the beginning of the study, after 7 days during the study and at the end of the post observation period. The animals were daily observed for clinical signs and mortality. Animals that died during the study and the surviving animals sacrificed at the end of the post observation period were necropsied and macroscopically examined.

At the analytical concentration of 2.23 mg/L all animals survived and did not show any clinical signs related to DMF exposure. In the other three treatment groups dyspnoea (irregular or intermittent respiration) and rough fur were observed as well in 3 females at 5.1 mg/L a minimal alopecia at the head. Deaths occurred 3 days after the start of the study: at 4.92 mg/L 2 of 10 males and 1 of 10 females died, at 5.1 mg/L all animals survived and at 5.85 mg/L 3 of 10 males and no female animal died.

Surviving animals recovered 6 -7 days after exposure. These animals did not show any gross lesions at necropsy, whereas the animals that died during the study had some organ findings, e.g. discoloration of the liver, haemorrhage in thymus and punctate haemorrhage in pancreas and in the gastric mucous membrane.

DMF is considered to be of low acute toxicity. Irregular or intermittent respiration were observed in the treated animals. LD50 for both sexes was determined to be >5.85 mg/L air

In an acceptable well-documented study (non-GLP, non-OECD), which meets basic scientific principles, the inhalation toxicity of an atmosphere saturated with vapours of N,N-dimethylformamide (DMF) in Wistar and Fischer rats was evaluated. Rats were exposed to 12 mg/L nominal ( Analytical: Fisher 344 rats: 9.6 ± 0.34 mg/L; Wistar rats: 9.8 ± 0.27 mg/L) for 1, 3, and 7 h. A 7 day post-exposure time followed. Clinical signs and necropsy of dead/sacrificed animals were observed.

The inhalation of a highly enriched/saturated vapour-air-mixture may represent an acute hazard (mortality within 3 h).

There is indication that the test substance causes local irritation to exposed tissue including the respiratory tract.


Justification for selection of acute toxicity – oral endpoint
Best study available.

Justification for selection of acute toxicity – inhalation endpoint
The most well-documented study with a maximum attainable concentration of DMF.

Justification for selection of acute toxicity – dermal endpoint
A well documented study available.

Justification for classification or non-classification

The available data for DMF indicate a relative low potential for acute toxicity. Since LD50 for oral route is 3010 mg/kg bw, no classification and labelling for the oral route is warranted in accordance to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations (EC) No 1272/2008.

In the key inhalation study, LC50 > 5.85 mg/L (vapour) was reported. In the key dermal study, LD50 > 3160 mg/kg bw was reported. DMF is harmonised classified according to Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation), as acute Tox Cat. 4 - H332 (Harmful if inhaled) and H312 (harmful in contact with skin).