Registration Dossier

Administrative data

Description of key information

Oral LD50: 4800-5830 mg/kg bw (rat), 4610-6020 mg/kg bw (mouse), 2820 mg/kg bw (rabbit).
Inhalation LC50 (rat, 4h) estimated to be 2.2 mg/L (for aerosol).
Dermal LD50 (rabbit): 2100 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (no details about the test substance or decrease in body weight; no non-lethal dose in females; no necropsy at termination).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC) No details available.
Species:
rat
Strain:
other: ChR-CD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: young adult rats
- Weight at study initiation: males 198-224 g, females 166-183 g

No further details available.


Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
50 % solution in water; average of 2.17-2.84 mL per male rat or 1.58-2.05 mL per female rat
Doses:
5000, 5500, 6000, 6500 mg/kg bw in males
4500, 5000, 5500, 6000 mg/kg bw in females
No. of animals per sex per dose:
10 rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14-15 days
- Observations (frequency): yes (presumably daily)
- Weighing: yes, but no details
- Necropsy of survivors performed: no
- Sacrifice: 14-15 days after application
Statistics:
Probit analysis (Finney)
Sex:
male
Dose descriptor:
LD50
Effect level:
5 810 mg/kg bw
Remarks on result:
other: 95% CL not defined
Sex:
female
Dose descriptor:
LD50
Effect level:
4 930 mg/kg bw
Remarks on result:
other: 95% CL not defined
Mortality:
Details are presented in Table 1.
In males 3/10 animals died at 5500 mg/kg bw, 9/10 at 6000 mg/kg bw and 7/10 at 6500 mg/kg bw. No males died at 5000 mg/kg bw.
In females 4/10 animals died at 4500 mg/kg bw, 2/10 at 5000 mg/kg bw, 9/10 at 5500 mg/kg bw and 10/10 at 6000 mg/kg bw.
Clinical signs:
Belly-to-cage posture; wet and/or stained mouth, nose and perineal area; eyes half closed; diarrhea, tremors, piloerection, pallor, prostration, lethargy, chromodacryorrhea and cyanosis were noted.
Body weight:
There was weight loss in all treatment groups (no details given)
Gross pathology:
No data

Table 1: Mortality in male and female ChR-CD rats after gavage within the post exposure observation period of 14 days

 Dose (mg/kg bw)  Mortality in males  Mortality in females
 6500  7/10 not tested
 6000  9/10  10/10
 5500  3/10   9/10
 5000  0/10  2/10
 4500  not tested   4/10
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 = 5810 mg/kg bw (males); LD50 =and 4930 mg/kg bw (females).
Executive summary:

Groups of 10 ChR-CD rats per sex per dose were gavaged with 4500 - 6500 mg/kg bw (4 dose levels per sex). The post exposure observation period was 2 weeks.

Male rats died at a dose level >=5500 mg/kg bw and no mortality was found at 5000 mg/kg bw. In females even at the low dose level lethal effects were seen.

Clinical signs like belly-to-cage posture, wet and/or stained mouth, nose and perineal area, half closed eyes, diarrhea, tremors, piloerection, pallor, prostration, lethargy, chromodacryorrhea, and cyanosis were recorded.

Conclusion: In male ChR-CD rats the oral LD50 was 5810 mg/kg bw and in females 4930 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is comparable to OECD Guideline 401 with acceptable restrictions (partly limited documentation, e.g. no data about animal strain or purity of test substance).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Purity unspecified
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
Source: Firma Gassner, Sulzfeld, Germany
Initial body weight: 166-266 g in males, 160-210 g in females

No further details available.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Concentration in test solution was 30 %; no data about fasting prior to application.

Doses:
4000, 5000, 5700, 6400, 8000, 10000 µL/kg bw (corresponding to 3760, 4700, 5360, 6020, 7520, 9400 mg/kg bw)
No. of animals per sex per dose:
10 rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Weighing: no data
- Necropsy of survivors and deceased animals
Statistics:
LD50 was estimated; no data about confidence limits.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 5 830 mg/kg bw
Remarks on result:
other: males and females combined
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 360 - < 6 020 mg/kg bw
Remarks on result:
other: estimation related to tabulated data
Sex:
male
Dose descriptor:
LD50
Effect level:
> 6 020 - < 7 520 mg/kg bw
Remarks on result:
other: estimation related to tabulated data
Mortality:
Data on mortality are presented in the Table 1.
At 6020, 7520 and 9400 mg/kg bw 10/10 females died, mostly within 1-2 days after application. 3/10 males died at 6020 mg/kg bw, 9/10 at 7520 mg/kg bw and 10/10 at 9400 mg/kg bw within 1 -7 days after application
No mortalities occurred at 3760, 4700, 5360 mg/kg bw.
Clinical signs:
Clinical signs at ≥ 7520 mg/kg bw, unexcited behaviour immediately after application, staggered gait, chewing behaviour, after ca. 3 h prone position, later: side position, reddened eyes, dyspnoe, death.
At 6020 mg/kg bw similar clinical signs plus ruffled coat and in females jerks and convulsions.
At ≤ 5360 mg/kg bw similar clinical signs as noted in the next higher dose level, except jerks and convulsions
Body weight:
No data available on body weight at study termination.
Gross pathology:
Surviving rats: no treatment related effects.
Deceased animals: smeared muzzles, 2 rats with dystelectatic lungs, ectasia of the stomach and gastrorrhagia, erosions of the gastric mucosa; diarrhoea
Other findings:
No

Table 1: Acute toxicity in male (m) and female (f) rats after oral application of dimethylacetamide

Dose

(mg/kg bw)

Number of rats which died within

1 hour

24 hours

48 hours

7 days

14 days

9400

0/10 f
0/10 m

8/10 f
2/10 m

10/10 f
9/10 m

10/10 f
10/10 m

10/10 f
10/10 m

7520

0/10 f
0/10 m

5/10 f
0/10 m

10/10 f
3/10 m

10/10 f
9/10 m

10/10 f
9/10 m

6020

0/10 f
0/10 m

4/10 f
0/10 m

9/10 f
1/10 m

10/10 f
3/10 m

10/10 f
3/10 m

5360

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

4700

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

3760

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

0/10 f
0/10 m

Interpretation of results:
GHS criteria not met
Conclusions:
LD50 ca. 5830 mg/kg bw (males/females combined)
Executive summary:

Groups of 10 male and 10 female rats were gavaged with 30 % aqueous solutions at dose levels of 3760, 4700, 5360, 6020, 7520, 9400 mg/kg bw. The post exposure observation period was 14 days.

At 6020, 7520 and 9400 mg/kg bw 10/10 females died, mostly within 1-2 days after application. 3/10 males died at 6020 mg/kg bw, 9/10 at 7520 mg/kg bw and 10/10 at 9400 mg/kg bw within 1 -7 days after application No mortalities occurred at 3760, 4700, 5360 mg/kg bw.

Clinical signs like low arousal behaviour immediately after application, staggered gait, chewing behaviour, prone position, later side position, ruffled coat, reddened eyes, and dyspnoe were observed prior to death. At 6020 mg/kg bw in females additionally jerks and convulsions were found.

Necropsy revealed no treatment related effects in survivors; rats found dead showed smeared muzzles, dystelectatic lungs (2 rats), ectasia of the stomach and gastrorrhagia, erosions of the gastric mucosa, and diarrhoea.

Conclusion: The oral LD50 was ca. 5830 mg/kg bw in male and female rats combined.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (limited documentation, e.g. no details about test substance, clinical signs; no necropsy; only females).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
no details available
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
20-50 % aqueous solution
Doses:
1600, 3200, 4000, 5000, 6400, 12500 µL/kg bw
No. of animals per sex per dose:
10 female rats
Control animals:
no
Details on study design:
Post exposure observation period: 14 days
Sex:
female
Dose descriptor:
LD50
Effect level:
4 800 mg/kg bw
95% CL:
4 200 - 5 470
Remarks on result:
other: corresponding to 5100 µL/kg bw
Mortality:
All rats died after ≥6400 µL/kg bw
3/10 rats died after 5000 µL/kg bw
1/10 rats died after 4000 µL/kg bw
No mortality was noted at ≤ 3200 µL/kg bw
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 = 4800 mg/kg bw (female rats).
Executive summary:

Groups of 10 female Sprague-Dawleyr ats were gavaged with aqueous solutions at 1600, 3200, 4000, 5000, 6400, 12500 µL/kg bw (concentration in water of 20 -50 %). The post exposure observation period was 14 days.

All rats died after6400 µL/kg bw, 3/10 rats died after 5000 µL/kg bw and 1/10 rats died after 4000 µL/kg bw. No mortality was noted at3200 µL/kg bw.

No data on clinical signs, body weight changes or necropsy.

Conclusion: The oral LD50 was ca. 5100 µL/kg bw for female rats corresponding to a dose level of 4800 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (no details about the test substance; only 3 doses; only males)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Identification: 220 RD 79, from S. Charlston
- Name of test material: dimethylacetamide (DMAC)
Species:
rat
Strain:
other: Carworth-Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: own colony
- Weight at study initiation: 90-120 g
- Age at study initiation: 5-6 weeks old

No futher details available.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
20 % test substance in corn oil
Doses:
Doses differed by a factor of 2.0 in geometric series
4, 8, 16 g/kg bw
No. of animals per sex per dose:
5 rats
Control animals:
no
Details on study design:
Post exposure observation period: 14 days
Necropsy was performed.
Clinical signs were recorded.
Statistics:
LD50 was calculated according to Thompson's method.
Sex:
male
Dose descriptor:
LD50
Effect level:
5 630 mg/kg bw
Remarks on result:
other: 95% CL not given because mortality ratios not fractional
Mortality:
Within 24 h all rats died at mid and high dose level (8 and 16 g/kg bw, respectively). There was no mortality at 4 g/kg bw.
Clinical signs:
8 g/kg bw: slight tremor and sensitivity to noise were noted.
16 g/kg bw: tremor and laboured breathing were observed.
Body weight:
There was an increase in body weight in the low dose group (all rats died in other dose groups).
Gross pathology:
Congestion of liver, lung, intestine, adrenals and kidney (pale kidney), liver mottled.
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 = 5630 mg/kg bw (male rats).
Executive summary:

Groups of 5 male Carworth-Wistar rats were gavaged with 4, 8, or 16 g/kg bw. The post exposure observation period was 14 days.

All rats died within one day at the mid and high dose levels but no mortality was seen after 4 g/kg bw.

Clinical signs were sensitivity to noise, tremor and labored breathing.

No effects on body weight was found in survivors.

Necropsy revealed congestion, pale kidney and mottled liver.

Conclusion: In male rats the oral LD50 was 5630 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Listed Range-Finding Toxicity Data without detailed documentation (e.g. no details on test substance or concentration in vehicle; dose levels not clearly specified, no data on clinical signs or necropsy).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Carworth-Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: rats raised in the authors own colony
- Diet: Rockland rat diet complete
- Initial body weight: 90-120 g
- Fasting period before study: no

No further details available.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
No details
Doses:
Dosages in a logarithmic series (no further data)
No. of animals per sex per dose:
5 male rats
Control animals:
no
Details on study design:
Post exposure observation period: 14 days
Statistics:
The LD50 value and its fiducial range were estimated according to the method of Thompson (Bact. Rev. 11 :115, 1947) using the tables of Weil (Biometrics 8 :249, 1952).
Sex:
male
Dose descriptor:
LD50
Effect level:
5 680 mg/kg bw
Mortality:
only the LD50 value was given
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Conclusions:
LD50 = 5680 mg/kg bw (male rats).
Executive summary:

Only a short statement is given on the acute oral toxicity in rats without any detailed information on the experimental procedure or individual results:

LD50 = 5680 mg/kg bw (male rats).

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (no details about the test substance or dose levels; post exposure observation period 7 days; no necropsy, no data about clinical signs).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
(7 days post exposure observation period)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Purity: pure
- Name of test material: dimethylacetamide (DMAC)
No further details available.
Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 15-25 g

No further details available.

Route of administration:
oral: gavage
Vehicle:
physiological saline
Details on oral exposure:
Application volume: 20 mL/kg bw
Doses:
At least 3 doses between LD16 and LD84;
no further data.
No. of animals per sex per dose:
5 mice
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no
- No data about clinical signs, body weight
Statistics:
Probit analysis (Finney)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4 610 mg/kg bw
95% CL:
>= 4 040 - <= 5 170
Remarks on result:
other: males and females combined
Mortality:
Mortality occurred within 3 days.
Females were more sensitive than males (no further details).
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Other findings:
No
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 = 4160 mg/kg bw (male/female).
Executive summary:

The substance was administered under standardized conditions to groups of 10 mice (5 females, 5 males) at doses that supplied at least 3 values lying between the LD16 and LD84. The median lethal dose and slope were determined with the aid of Finney's programmed probit analysis. Mortality occurred within 3 days. Females were more sensitive than males (no further details). A LD50 value of4610 mg/kg bw in male and female NMRI mice was reported.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is comparable to OECD Guideline 401 with acceptable restrictions (partly limited documentation, e.g. no data about purity of test substance).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.
Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
Source: Firma Gassner, Sulzfeld, Germany
Initial body weight: 25.0-30.2 g in males, 24.8-30.2 g in females

No further details available
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Concentration in test solution was 2 (200 µL/kg bw), 20 (1600 µL/kg bw), or 30 % (all other dose levels); no data about fasting prior to application.

Doses:
200, 1600, 3200, 4000, 5000, 5700, 6400, 8000, 10000 µL/kg bw (corresponding to 190, 1500, 3000, 3760, 4700, 5360, 6020, 7520, 9400 mg/kg bw)
No. of animals per sex per dose:
5 mice
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Weighing: no data
- Necropsy of survivors and animals found dead
Statistics:
LD50 was estimated; no data about confidence limits.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 6 020 mg/kg bw
Remarks on result:
other: males and females combined
Sex:
female
Dose descriptor:
LD50
Effect level:
> 6 020 - < 7 520 mg/kg bw
Remarks on result:
other: estimation related to tabulated data
Sex:
male
Dose descriptor:
LD50
Effect level:
> 3 760 - < 4 700 mg/kg bw
Remarks on result:
other: estimation related to tabulated data
Mortality:
Data on mortality are presented in Table 1. At the high dose level, all animals died within a few hours and at 7520 mg/kg bw within 24 h; at ≤ 6020 mg/kg bw, mice died 1-2 days after application. Males seem to be more sensitive than females.
Clinical signs:
Apathy, dyspnoe, death.
No symptoms were noted at ≤1600 mg/kg bw.
Body weight:
No data are available on body weight at study termination.
Gross pathology:
Surviving animals showed no treatment related effects.
Mice found dead showed gastrorrhagia, other effects were not clearly treatment related.

Table 1: Acute toxicity in male (m) and female (f) mice after oral application of dimethylacetamide

Dose

(µL/kg bw)

Number of rats which died within

1 hour

24 hours

48 hours

7 days

14 days

10000

0/5m
0/5f

5/5m
5/5f

5/5m
5/5f

5/5m
5/5f

5/5m
5/5f

8000

0/5m
0/5f

5/5m
5/5f

5/5m
5/5f

5/5m
5/5f

5/5m
5/5f

6400

0/5m
0/5f

2/5m
2/5f

3/5m
2/5f

3/5m
2/5f

3/5m
2/5f

5000

0/5m
0/5f

3/5m
0/5f

4/5m
0/5f

4/5m
0/5f

4/5m
0/5f

4000

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

3200

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

1600

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

200

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

0/5m
0/5f

Interpretation of results:
GHS criteria not met
Conclusions:
LD50 ca. 6020 mg/kg bw (male/female combined)
Executive summary:

Groups of 5 male and 5 female NMRI mice were gavaged with aqueous solutions at dose levels of 190, 1600, 3000, 3760, 4700, 5360, 6020, 7520, 9400 mg/kg bw (concentration in water of 2-30 %). The post exposure observation period was 14 days.

At the high dose level all animals died within a few hours and at 7520 mg/kg bw within 24 h; at 6020 mg/kg bw mice died 1-2 days after application. Males seemed to be more sensitive than females.

Clinical signs like apathy and dyspnoe were observed prior to death. No clinical signs were detected at 1600 mg/kg bw.

Necropsy revealed no treatment related effects in survivors; mice found dead showed gastrorrhagia.

Conclusion: The oral LD50 was ca. 6020 mg/kg bw for male and female mice combined.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (limited documentation, e.g. no details about test substance, clinical signs; no necropsy; only females).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.
Species:
mouse
Strain:
NMRI
Sex:
female
Details on test animals and environmental conditions:
No further details available
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
20-30 % aqueous solution
Doses:
3200, 4000, 5000, 6400, 8000, 10000 µL/kg bw
No. of animals per sex per dose:
10 mice
Control animals:
no
Details on study design:
Post exposure observation period: 14 days
Sex:
female
Dose descriptor:
LD50
Effect level:
6 000 mg/kg bw
Remarks on result:
other: corresponding to 6400 µL/kg bw
Mortality:
All mice died after ≥8000 µL/kg bw
5/10 mice died after 6400 µL/kg bw
4/10 mice died after 5000 µL/kg bw
There was no mortality at ≤ 4000 µL/kg bw.
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 = 6000 mg/kg bw (female).
Executive summary:

Groups of 10 female NMRI mice were gavaged with aqueous solutions at 1 3200, 4000, 5000, 6400, 8000, 10000 µL/kg bw (concentration in water of 20 -30 %). The post exposure observation period was 14 days.

All mice died after≥8000 µL/kg bw, 5/10 mice died after 6400 µL/kg bw and 4/10 mice died after 5000 µL/kg bw. No mortality was noted at≤4000 µL/kg bw.

No data on clinical signs, body weight changes or necropsy.

Conclusion: The oral LD50 was ca. 6400 µL/kg bw for female rats corresponding to a dose level of 6000 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study comparable to OECD Guideline 401 with acceptable restrictions (clinical signs not daily documented, only 2 animals per dose, imbalanced sex ratio).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Purity: 99.9 %
No further details available.
Species:
rabbit
Strain:
other: mongrel
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Firma Heinrich Metz, Waldhilbersheim, Germany
- Initial body weight: mean 2.95 kg
- Food and water: certified diet and water ad libitum

No further details available.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
10, 20, or 80 % test substance solutions in water were administered (see Table 1)
Doses:
1000, 2000, 4000, 8000 µL/kg bw (corresponding to 940, 1880, 3760, 7520 mg/kg bw)
No. of animals per sex per dose:
2 males at 8000 and 2000 µL/kg bw
1 male and 1 female at 1000 and 4000 µL/kg bw
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: presumably daily but documentation not available for each day
- Weighing: several times during post exposure observation period
- Necropsy: survivors and animals found dead
Statistics:
Estimation of LD50
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 2 820 mg/kg bw
Remarks on result:
other: males and females combined; corresponding to 3000 µL/kg bw
Mortality:
8000 µL/kg bw: animals died within 2-3 hours
4000 µL/kg bw: animals died within 1-2 days
<= 2000 µL/kg bw: no death
Clinical signs:
8000 µL/kg bw: atony, increased respiratory rate, convulsions, death
4000 µL/kg bw: reduced appetite, dyspnoea
2000 µL/kg bw: reduced appetite, slight apathy, diarrhoea in 1 rabbit (temporary)
1000 µL/kg bw: no effects
Body weight:
8000 µL/kg bw: animals died within 2-3 hours
4000 µL/kg bw: died within 1-2 days
≤ 2000 µL/kg bw: slight decrease in body weight
Gross pathology:
Rabbits found dead: in 2 rabbits, bloody smear on the gastric mucosa was noted.
Survivors: no effects

Table 1: Acute toxicity in rabbits after oral application of dimethylacetamide

Dose (µL/kg bw)

Concentration (%)

Mortality

8000

80

2/2

4000

20

2/2

2000

20

0/2

1000

10

0/2

Interpretation of results:
GHS criteria not met
Conclusions:
LD50 = 2820 mg/kg bw.
Executive summary:

Groups of 2 rabbits (males or females) were gavaged with 10, 20 or 80 % aqueous solutions at dose levels of 1000, 2000, 4000 or 8000 µL/kg bw (940, 1880, 3760, 7520 mg/kg bw). The post exposure observation period was 14 days.

At the high dose level both rabbits died within 2-3 h and at 4000 µL/kg bw animals died within 1-2 days; no deaths were seen at lower dose levels.

Clinical signs like atony, increased respiratory rate, convulsions occurred prior to death.

Necropsy revealed treatment related bloody smear on the gastric mucosa in animals found dead but no effects in survivors.

Conclusion: The authors estimated an oral LD50 in rabbits of 3000 µL/kg bw corresponding to 2820 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is comparable to OECD Guideline 401 with acceptable restrictions (partly limited documentation, e.g. no details about the test substance).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.
Species:
dog
Strain:
other: Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Wiga, Sulzfeld, Germany
- Weight at study initiation: mean body weight: 11.8 kg in males, 11.0 kg in females
- Certified diet: ad libitum

No further details available.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Aqueous solution, concentration 2.5, 5, 10, 20 %.
Doses:
250, 500, 1000, 2000 µL/kg bw (corresponding to 235, 470, 940, 1900 mg/kg bw)
No. of animals per sex per dose:
2-4 dogs
Control animals:
no
Details on study design:
Post exposure observation period: 14 days
Necropsy was performed.
Hematology and clinical chemistry (n=2 per dose; 4 samples/dog; sampling prior to treatment, no further details about blood sampling)
Statistics:
no data
Sex:
not specified
Dose descriptor:
LDLo
Effect level:
470 mg/kg bw
Remarks on result:
other: 1 out of 4 dogs died, effects on liver enzymes at >= 470 mg/kg bw
Mortality:
see Table 1
One out of 4 dogs died at 470 mg/kg bw and all dogs at 940 mg/kg bw. One out of 2 dogs died at 1900 mg/kg bw. One dog of the high dose level survived, but this animal vomited after application of the test substance.
Clinical signs:
235 mg/kg bw: no effects
470 mg/kg bw: one dog refused food consumption at day 2 and showed bleeding of the nose; this animal died on day 4.
≥ 940 mg/kg bw: vomiting at day 1-2, no food consumption, extensor spasms, bleeding of the nose, death at day 3-4.
Body weight:
no data
Gross pathology:
Dogs found dead: effects were not clearly treatment related but liver with mottled liver lobules (yellow-brown colour) was noted.
Survivors: there were no (clearly) treatment related effetcs.
Other findings:
Haematology: there were no effects.
Clinical chemistry: there were no effects except alterations in liver enzyme activity indicating hepatotoxic effects.

Table 1: Mortality in dogs after gavage (no data about sex)

 Dose (mg/kg bw)  Mortality
 235  0/2
 470  1/4
 940  2/2
 1900  1/2
Interpretation of results:
study cannot be used for classification
Remarks:
Weiss et al. (1962, see section 7.10.3) reported toxicity but no mortality when doses up to 610 mg/kg bw were given intravenously to tumor patients. This indicates that the acute oral study in the dog rather overestimates the acute lethal potential and should be considered as non-relevant with regard to the classification of DMAC's acute oral toxicity according to Regulation (EC) No 1272/2008. Nevertheless, the NOAEL of 235 mg/kg bw derived from the acute toxicity study in dogs could be taken into consideration for the derivation of an acute/short-term oral DNEL.
Conclusions:
LDLo = 470 mg/kg bw.
Executive summary:

Beagle dogs were gavaged once with 235, 470, 940, 1900 mg/kg bw (2, 4, 2, 2 dogs per dose level, respectively).

One out of 4 dogs died at 470 mg/kg bw and all dogs at 940 mg/kg bw. One out of 2 dogs died at 1900 mg/kg bw. One dog of the high dose level survived, but this animal vomited after application of the test substance.

Clinical signs were refused food consumption, extensor spasms, bleeding of the nose, and death at day 3 -4. No clinical signs were detected at 235 mg/kg bw.

No effects were found at hematology but clinical chemistry suggested altered liver function.

Necropsy of dogs found dead supported effects on the liver.

Conclusion: The LDLo in Beagle dogs was 470 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 830 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study is comparable to Guideline study with acceptable restrictions (partly limited documentation, e.g. no details about the test substance; recommended limit concentration reached but exposure duration 1 h; conspicuous variations in dose levels; exclusive exposure to vapour not clear).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
(1 h exposure)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
- Batch No.: Haskell No. 12,346
No further details available.
Species:
rat
Strain:
other: ChR-CD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 235-265 g in males, 180-220 g in females
- Fasting period before study: no data, but no water and no diet were provided during exposure
- Housing: two rats per cage
- Diet and water ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
No details available.
Route of administration:
other: Vapour, but aerosol generation not excluded
Type of inhalation exposure:
whole body
Vehicle:
other: houseline air
Details on inhalation exposure:
The test substance was syringe-driven into a spraying system nebulizer; standards and samples were prepared in absolute ethanol; a Beckman Model 25 Spectrophotometer was used for analysing concentration; sampling was performed every 10 minutes; comparison with standard curve.
Authors stated that 8.8 mg/L was the max. vapour concentration at room temperature (25 °C), no higher concentrations available at this temperature.
4 rats of each sex were exposed in a stainless steel exposure chamber.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
(results are presented below, see concentrations)
Duration of exposure:
1 h
Concentrations:
Time weighted average: 3.4 (measured range 2.4-4.8), 5.8 (3.8-22.9), or 8.8 (6.6-13.0) mg/L
No. of animals per sex per dose:
8 rats
Control animals:
no
Details on study design:
- Post exposure observation period: 14 days
- Frequency of observations and weighing: yes, but no details
- Necropsy of survivors performed: no
- Other examinations performed: no
Statistics:
No data
Sex:
female
Dose descriptor:
LC50
Effect level:
8.8 mg/L air
Exp. duration:
1 h
Remarks on result:
other: estimated LC50
Sex:
male
Dose descriptor:
LC0
Effect level:
8.8 mg/L air
Exp. duration:
1 h
Remarks on result:
other: max. available vapour concentration
Mortality:
Females were more susceptible than males, 4/8 females treated at 8.8 mg/L died within 2 days postexposure. There was no mortality in any other group.
Clinical signs:
No clinical signs were noted in males; females were more susceptible than males: at the low and mid dose level (3.4 and 5.8 mg/mL) hyperactivity was observed the first week post exposure; there was no hyperactivity at the high dose level of 8.8 mg/mL (no further signs were reported).
Body weight:
Males
There were no effects at the low dose of 3.4 mg/L;
at 5.8 mg/L, there was initial body weight loss (5-10 %) within 48 h and thereafter body weight gain;
at 8.8. mg/L, there was initial body weight loss (20 %) and thereafter body weight gain.

Females
At 3.4 and 5.8 mg/L, there was no relevant effect on body weight;
at 8.8 mg/L, there was body weight loss (15 %) in survivors within 48 h.
Gross pathology:
No data
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LC50(1 hour) of DMAC was determined to be 8.8 mg/L in female rats. Female rats were more susceptible than males.
Executive summary:

Groups of 8 male and 8 female ChR-CD rats were exposed for 1 h to time weighted concentrations of: 3.4 (measured range 2.4-4.8), 5.8 (3.8-22.9), or 8.8 (6.6-13.0) mg/L. The test substance was syringe-driven into a spraying system nebulizer. The post exposure observation period was 14 days. No mortality was found in males at any exposure concentration. Females were more susceptible than males. At 8.8 mg/L 4 out of 8 females died within 48 h but no deaths were seen at the low and mid dose level. No clinical signs were recorded except hyperactivity in females on day 3-7 after exposure. Initial reduction in body weight was detected in males at >= 5.8 mg/L and in females at 8.8 mg/L. Conclusion: The LC50 (1 h) in female rats was estimated to be 8.8 mg/L; no mortality was seen in male rats at the time weighted average of 8.8 mg/L. The LC50(1 hour) of DMAC was determined to be 8.8 mg/L in female rats. Female rats were more susceptible than males. However, in this study conspicuous variations in dose levels were obvious and exclusive exposure to vapour (as mentioned by the authors) was not clear.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study is comparable with the inhalation hazard test described in the Annex of OECD Guideline 403 (adopted 1981) with acceptable restrictions (post exposure observation period of 7 days [but no systemic symptoms recorded]; no data about strain of test animals).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Principles of method if other than guideline:
Study is comparable with the inhalation hazard test described in the Annex of OECD Guideline 403 (adopted 1981).
GLP compliance:
no
Test type:
other: acute inhalation hazard test
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
- Purity: 99.9 %
No further details available.
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
Initial mean body weights in Trial 1: 225 g (males), 160 g (females)
Initial mean body weights in Trial 2: 157 g (males and females)

No further details available.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
Vapour was generated by bubbling 200 L/h of dry air (no carbon dioxide) through the liquid test substance column (volume ca. 50 mL) of about 5 cm above a fritted glass disc in a glass cylinder at a temperature of 20°C (Trial 1) or 50°C (Trial 2).

Trial 1:
3 rats/sex were exposed to vapour generated at 20°C.

Trial 2:
12 rats were exposed to vapour generated at 50°C; exposure started for the first subgroup of 6 rats (presumably 3 males and 3 females) on 10-Nov-1969 (termination 7 days later) and for the second subgroup of 6 rats (presumably 3 males and 3 females) on 11-Nov-1969 (termination 7 days later).
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
8 h
Concentrations:
Estimation of concentration from the amount of test substance consumed and the air volume used was given.
Trial 1: 5.2 mg/L
Trial 2: 13.1 and 12.3 mg/L, mean 12.7 mg/L
No. of animals per sex per dose:
Trial 1: 3 rats
Trial 2: 6 rats [totally 12 rats were used (presumably 6 males and 6 females).]
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations: daily
- Weighing: initial and terminal body weight
- Necropsy of survivors was performed at termination
Statistics:
No data
Sex:
male/female
Dose descriptor:
LC0
Effect level:
5.2 mg/L air (nominal)
Exp. duration:
8 h
Remarks on result:
other: estimated value; saturated vapour at 20°C
Sex:
male/female
Dose descriptor:
LC0
Effect level:
12.7 mg/L air
Exp. duration:
8 h
Remarks on result:
other: estimated value, saturated vapour at 50°C
Mortality:
There was no mortality.
Clinical signs:
There were no clinical signs, except eye irritation and eyelid closure during the exposure (no effects recorded the next day).
Body weight:
There was body weight gain in all subgroups.
Gross pathology:
No effects were detected at necropsy of survivors.
Interpretation of results:
GHS criteria not met
Conclusions:
The LC0(8 hours) of DMAC vapour was determined to be 5.2 (20 °C) and 12.7 mg/L (50 °C) in male and female rats.
Executive summary:

In the inhalation hazard test rats were exposed for 8 h to saturated DMAC vapour generated at 20 or 50°C (liquid substance). The post exposure observation period was 7 days. No mortality occurred in any trial. No clinical signs were detected except eye irritation and eyelid closure during the exposure (no effects recorded the next day). Necropsy revealed no treatment related effects. In the inhalation hazard test no effects were detected in male and female rats after exposure for 8 h to saturated vapour generated at 20°C (estimated concentration 5.2 mg/L) or 50°C (12.7 mg/L). The LC0(8 hours) of DMAC vapour was determined to be 5.2 (20 °C) and 12.7 mg/L (50 °C) in male and female rats.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Study is comparable with the inhalation hazard test described in the Annex of OECD Guideline 403 (adopted 1981) with acceptable restrictions (partly limited documentation; only males tested)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
no
Test type:
other: inhalation hazard test
Limit test:
yes
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.
Species:
rat
Strain:
other: albino, no further data
Sex:
male
Details on test animals and environmental conditions:
no details available
Route of administration:
inhalation: vapour
Type of inhalation exposure:
other: no data, presumably whole body
Vehicle:
other: air
Details on inhalation exposure:
Rats were exposed to a flowing stream of air approaching saturation with test substance vapour; a stream was prepared by passing dried air through a fritted disc gas washing bottle, initially at room temperature.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
8 h
Concentrations:
Saturated test substance vapour
No. of animals per sex per dose:
6 males
Control animals:
no
Details on study design:
Inhalation exposures continued for periods of time in an essentially logarithmic series with a ratio of two, extending to eight hours, until the period killing half the rats within 14 days of inhalation was defined.
Statistics:
No data
Sex:
male
Dose descriptor:
LC0
Effect level:
> 7.16 mg/L air
Exp. duration:
8 h
Remarks on result:
other: saturated vapour; no mortalities occurred
Mortality:
No mortality occurred during the post exposure observation period of 14 days.
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Other findings:
No
Interpretation of results:
GHS criteria not met
Conclusions:
The LC0(8 hours) of saturated DMAC vapour was determined to be >7.16 mg/L in male rats.
Executive summary:

Six male albino rats were exposed in an inhalation hazard test for 8 h to saturated vapour. The stream of air approaching saturation with vapours was prepared by passing dried air through a fritted disc gas washing bottle at room temperature. The post exposure observation period was 14 days. No mortality was observed. The LC0(8 hours) of saturated DMAC vapour was determined to be >7.16 mg/L in male rats.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study is comparable with the inhalation hazard test described in the Annex of OECD Guideline 403 (adopted 1981) with acceptable restrictions (no details about test substance; only males; no data about strain). Determination of LC50 not possible with further experimental data using aerosol (only 2 concentrations; no analysis of concentration).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
(Annex)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
No details available.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
Experiment 1:
Concentrated test substance vapour was generated in a glass washing bottle by passing dried air at 2.5 L/min through a fritted glass disc immersed to a depth of at least 1-1/2 inches (approximately 2.5-1.3 cm) in the test substance which was delivered to rats in a 9-L glass chamber (vapour exposure).

Experiment 2:
Nebulised test substance was diluted 3-fold with air (aerosol exposure).
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
8 h
Remarks on duration:
8h in Exeriment 1, 4 h in Experiment 2
Concentrations:
Experiment 1: saturated vapour at room temperature (8-h exposure)
Experiment 2: 10.7 or 32.0 mg/L (4-h exposure)
No. of animals per sex per dose:
Experiment 1: 12 male rats
Experiment 2: 6 male rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy performed: yes
Statistics:
No data
Sex:
male
Dose descriptor:
LC0
Effect level:
other: saturated vapour
Exp. duration:
8 h
Remarks on result:
other: no mortality in 12 male rats
Sex:
male
Dose descriptor:
LCLo
Effect level:
10.7 mg/L air
Exp. duration:
4 h
Remarks on result:
other: 2/6 rats died (aerosol)
Sex:
male
Dose descriptor:
LC100
Effect level:
32 mg/L air
Exp. duration:
4 h
Remarks on result:
other: 6/6 rats died within 1 day (aerosol)
Mortality:
Experiment 1: There was no mortality.
Experiment 2: All animals (6/6 rats) died after 4-h exposure to 32 mg/L, and 2/6 rats died after 4-h exposure to 10.7 mg/L (within 1 day, except one low dose rat at Day 4).
Clinical signs:
Experiment 1: No data
Experiment 2: Inactivity was noted.
Body weight:
No data
Gross pathology:
Experiment 1: Slight lung congestion was observed.
Experiment 2: In rats found dead there was congestion of intestine; survivors showed no effects.
Other findings:
No
Interpretation of results:
GHS criteria not met
Conclusions:
Inhalation of saturated DMAC vapour for 8 hours resulted in no mortality.
The LCLo(4 hours) and the LC100(4 hours) of DMAC aerosol were determined to be 10.7 and 32.0 mg/L in male rats, under the conditions of this study.
Executive summary:

Groups of 12 rats were exposed for 8 h (Experiment 1; saturated vapour at room temperature), respectively 6 rats for 4 h (Experiment 2; 10.7 mg/L and 32 mg/L areosol exposure). The post exposure observation period was 14 days. In Experiment 1 no mortality was observed. In Experiment 2 all rats exposed to 32 mg/L died. From the animals exposed to 10.7 mg/L, 2/6 animals died during the course of the study.

Inhalation of saturated DMAC vapour for 8 hours resulted in no mortality. The LCLo(4 hours) and the LC100(4 hours) of DMAC aerosol were determined to be 10.7 and 32.0 mg/L in male rats, under the conditions of this study.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
2 200 mg/m³

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is comparable to OECD Guideline 402 with acceptable restrictions (partly limited documentation, e.g. no details on test substance; no data about systemic clinical signs; 4 animals per dose used, 5 per dose recommended in the Guideline).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
No details available.
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: ca. 2.5 kg
- Age at study initiation: 3-5 months old

No further details available.


Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The fur was closely clipped over the entire trunk; the dose was retained under an impervious plastic film; animals were immobilized during the exposure period.
Duration of exposure:
24 h
Doses:
1260, 2520, 5000 µL/kg bw (corresponding to 1180, 2370, 4700 mg/kg bw)
No. of animals per sex per dose:
4 rabbits
Control animals:
no
Details on study design:
Dosages greater than 20 mL/kg bw could not be retained in contact with the skin; after 24 h contact the impervious plastic film was removed.
Post exposure observation period: 14 days
Statistics:
The LD50 value and its fiducial range were estimated by the method of Thompson (Bact. Rev. 11 :115, 1947) using the tables of Weil (Biometrics 8 :249, 1952).
Sex:
male
Dose descriptor:
LD50
Effect level:
2 240 other: µL/kg bw
95% CL:
>= 1 230 - <= 4 110
Remarks on result:
other: corresponding to 2100 mg/kg bw
Mortality:
5 mL/kg bw: 4/4 rabbits died. One rabbit died within 60 minutes, the other 3 animals died after 1-3 days.
2.5 mL/kg bw: 2/4 rabbits died 2 and 5 days after application.
1.26 mL/kg bw: 1/4 rabbits died after 3 days.
Clinical signs:
Local effects were found noted including erythema, necrosis and desquamation.
There are no data about systemic effects.
Body weight:
Increased body weight was observed in most survivors except 2 rabbits of the low dose group.
Gross pathology:
Several rabbits that died had lung haemorrhage and speckled or pitted kidney surface; in one animal of the highest dose level, there was blood in the peritoneum.
Other findings:
No
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 of DMAC was determined to be 2100 mg/kg bw in male rabbits.
Executive summary:

Groups of 4 male New Zealand rabbits were dermally exposed to doses of 1.26, 2.5, or 5 mL/kg bw. The post exposure observation period was 14 days. One out of 4, 2/4, or 4/4 rabbits died after exposure, respectively. Local effects like erythema, necrosis, desquamation were recorded (no data about systemic effects). Necropsy of dead animals revealed lung hemorrhage, speckled or pitted kidney surface and blood in peritoneum. The dermal LD50 in male rabbits was 2240 µL/kg bw corresponding to 2100 mg/kg bw.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (pregnant rabbits used; partly limited documentation, e.g. no details about doses).
Qualifier:
equivalent or similar to
Guideline:
other: Approximate lethal dose procedures
GLP compliance:
no
Test type:
other: Approximate lethal dose procedures
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
- Purity: ≥98 %
No further details available.
Species:
rabbit
Strain:
New Zealand White
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Pregnant rabbits
- Body weight: ca 4 kg

No further details available.
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
One animal was used per dose level; rabbits were treated on gestation day 15 (GD15).
Duration of exposure:
Unwashed
Doses:
There was a factor of 1.5 between dose levels.

No further details available.
No. of animals per sex per dose:
1 female
Control animals:
no
Details on study design:
Animals were sacrificed on GD30.
Statistics:
No data
Sex:
female
Dose descriptor:
other: approximate lethal dose
Effect level:
5 000 mg/kg bw
Remarks on result:
other: pregnant rabbits
Mortality:
No data
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Other findings:
No
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal ALD of DMAC was determined to be 5000 mg/kg bw in pregnant rabbits.
Executive summary:

The approximate lethal dose in pregnant New Zealand White rabbits was determined. One rabbit per dose level received dermal application (coverage: open) at gestation day 15. The post exposure period was 14 days. In pregnant New Zealand White rabbits the approximate letal dose was 5000 mg/kg bw after dermal exposure.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (pregnant rats used; partly limited documentation, e.g. no details about doses).
Qualifier:
equivalent or similar to
Guideline:
other: Approximate lethal dose procedures
Deviations:
no
GLP compliance:
no
Test type:
other: Approximate lethal dose procedures
Limit test:
no
Specific details on test material used for the study:
- Name of test material: dimethylacetamide (DMAC)
- Purity: ≥98 %
No further details available.
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Primigravida rats
- Body weight: 220-250 g

No further details available.
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
One animal was used per dose level; rats were treated on gestation day 11 (GD11).
Duration of exposure:
Unwashed
Doses:
There was a factor of 1.5 between dose levels.

No further details available.
No. of animals per sex per dose:
1 female
Control animals:
no
Details on study design:
Animals sacrificed on GD20.
Statistics:
No data
Sex:
female
Dose descriptor:
other: approximate lethal dose
Effect level:
7 500 mg/kg bw
Remarks on result:
other: pregnant rats
Mortality:
No data
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Other findings:
No
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal ALD of DMAC was determined to be 7500 mg/kg bw in pregnant rats.
Executive summary:

The approximate lethal dose was also determined in pregnant Sprague-Dawley rats. One rat per dose level received dermal application (coverage: open) at gestation day 11. The post exposure period was 9 days. In pregnant Sprague-Dawley rats the approximate letal dose was 7500 mg/kg bw after dermal exposure.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 100 mg/kg bw

Additional information

In the OECD SIDS document (2001; SIAM 13) on N,N-dimethylacetamide (DMAC) data were presented on this endpoint which were also documented in this report. However, further studies relevant for evaluation were found which were not included in the OECD SIDS (2001). This might be related to the fact that the initial version of the OECD SIDS document was prepared for SIAM3 (1995). Delegates of SIAM3 criticised lacking information and these comments could still not be resolved at the meeting of SIAM12.

A bright set of studies is available for the endpoint acute toxicity for DMAC. In this endpoint summary only relevant studies are mentioned.

In the following the LD50 values for different species were reported in reliable studies. Lower LD50 values were documented in further studies in mice and rats but these studies are of limited validity (and therefore not reported in this summary).

Acute oral toxicity:

Rat

Groups of 10 male and 10 female rats were gavaged with 30 % aqueous solutions at dose levels of 3760, 4700, 5360, 6020, 7520, 9400 mg/kg bw. The post exposure observation period was 14 days. Females at 7520 mg/kg bw and all rats at the high dose level died within 2 days; at 7520 mg/kg bw males died within 2-7 days and at 6020 mg/kg bw rats died 1-7 days after application.Clinical signs like low arousal behaviour immediately after application, staggered gait, chewing behaviour, prone position, later side position, ruffled coat, reddened eyes, and dyspnoe were observed prior to death. At 6020 mg/kg bw in females additionally jerks and convulsions were found. Necropsy revealed no treatment related effects in survivors; rats found dead showed smeared muzzles, dystelectatic lungs (2 rats), ectasia of the stomach and gastrorrhagia, erosions of the gastric mucosa, and diarrhoea. Conclusion: The oral LD50 was ca. 5830 mg/kg bw in male and female rats combined (1970, RL2 [reliability]).

Groups of 10 ChR-CD rats per sex per dose were gavaged with 4500 - 6500 mg/kg bw (4 dose levels per sex). The post exposure observation period was 2 weeks. Male rats died at a dose level >=5500 mg/kg bw and no mortality was found at 5000 mg/kg bw. In females even at the low dose level lethal effects were seen. Clinical signs like belly-to-cage posture, wet and/or stained mouth, nose and perineal area, half closed eyes, diarrhea, tremors, piloerection, pallor, prostration, lethargy, chromodacryorrhea, and cyanosis were recorded. Conclusion: In male ChR-CD rats the oral LD50 was 5810 mg/kg bw and in females 4930 mg/kg bw (Kennedy & Sherman, 1986).

Groups of 5 male Carworth-Wistar rats were gavaged with 4, 8, or 16 g/kg bw. The post exposure observation period was 14 days. All rats died within one day at the mid and high dose levels but no mortality was seen after 4 g/kg bw. Clinical signs were sensitivity to noise, tremor and labored breathing. No effects on body weight was found in survivors. Necropsy revealed congestion, pale kidney and mottled liver. Conclusion: In male rats the oral LD50 was 5630 mg/kg bw (1955, RL2).

Ten female Sprague-Dawley rats were gavaged with 1600, 3200, 4000, 5000, 6400, 12500 µL/kg bw. Mortality was observed at >= 4000 µL/kg bw (3760 mg/kg bw). The oral LD50 in female rats was 4800 mg/kg bw (1976, RL2).

Mouse

Groups of 5 male and 5 female NMRI mice were gavaged with aqueous solutions at dose levels of 190, 1500, 3000, 3760, 4700, 5360, 6020, 7520, 9400 mg/kg bw (concentration in water of 2-30 %). The post exposure observation period was 14 days. At the high dose level all animals died within a few hours and at 7520 mg/kg bw within 24 h; at 6020 mg/kg bw mice died 1-2 days after application. Males seemed to be more sensitive than females. Clinical signs like apathy and dyspnoe were observed prior to death. No clinical signs were detected at 1500 mg/kg bw. Necropsy revealed no treatment related effects in survivors; mice found dead showed gastrorrhagia. Conclusion: The oral LD50 was ca. 6020 mg/kg bw for male and female mice combined (1970, RL2).

A similar but slightly lower oral LD50 value was reported by Bartsch et al. (1976): 4610 mg/kg bw in male and female NMRI mice.

Rabbit

Groups of 2 rabbits (males or females) were gavaged with 10, 20 or 80 % aqueous solutions at dose levels of 1000, 2000, 4000 or 8000 µL/kg bw (940, 1880, 3760, 7520 mg/kg bw). The post exposure observation period was 14 days. At the high dose level both rabbits died within 2-3 h and at 4000 µL/kg bw animals died within 1-2 days; no deaths were seen at lower dose levels. Clinical signs like atony, increased respiratory rate, convulsions occurred prior to death. Necropsy revealed treatment related bloody smear on the gastric mucosa in animals found dead but no effects in survivors. Conclusion: The authors estimated an oral LD50 in rabbits of 3000 µL/kg bw corresponding to 2820 mg/kg bw (1970, RL2).

Dog

There is evidence that the dog is the most sensitive species in acute oral toxicity. Beagle dogs were gavaged once with 235, 470, 940, 1900 mg/kg bw (2, 4, 2, 2 dogs per dose level, respectively). One out of 4 dogs died at 470 mg/kg bw and all dogs at 940 mg/kg bw. Clinical signs were refused food consumption, extensor spasms, bleeding of the nose, and death at day 3 -4. No clinical signs were detected at 235 mg/kg bw. No effects were found at hematology but clinical chemistry suggested altered liver function. Necropsy of dogs found dead supported effects on the liver. Conclusion: The LDlow in Beagle dogs was 470 mg/kg bw (1977, RL2).

Acute inhalation toxicity in rats:

In the inhalation hazard test rats were exposed for 8 h to saturated DMAC vapour generated at 20 or 50°C (liquid substance). The post exposure observation period was 7 days. No mortality occurred in any trial. No clinical signs were detected except eye irritation and eyelid closure during the exposure (no effects recorded the next day). Necropsy revealed no treatment related effects. Conclusion: In the inhalation hazard test no effects were detected in male and female rats after exposure for 8 h to saturated vapour generated at 20°C (estimated concentration 5.2 mg/L) or 50°C (12.7 mg/L) (1970, RL2).

In accord, the second inhalation hazard test gave similar results. Six male albino rats were exposed for 8 h to saturated vapour. The stream of air approaching saturation with vapours was prepared by passing dried air through a fritted disc gas washing bottle at room temperature. The post exposure observation period was 14 days. No mortality was observed (Smyth et al., 1962, RL4).

Groups of 8 male and 8 female ChR-CD rats were exposed for 1 h to time weighted concentrations of: 3.4 (measured range 2.4-4.8), 5.8 (3.8-22.9), or 8.8 (6.6-13.0) mg/L. The post exposure observation period was 14 days. No mortality was found in males at any exposure concentration. Females were more susceptible than males. At 8.8 mg/L 4 out of 8 females died within 48 h but no deaths were seen at the low and mid dose level. No clinical signs were recorded except hyperactivity in females on day 3-7 after exposure. Initial reduction in body weight was detected in males at >= 5.8 mg/L and in females at 8.8 mg/L. Conclusion: The LC50 (1 h) in female rats was estimated to be 8.8 mg/L; no mortality was seen in male rats at the time weighted average of 8.8 mg/L (Kennedy, 1986). However, in this study conspicuous variations in dose levels were obvious and exclusive exposure to vapour (as mentioned by the authors) was not clear.

Groups of 12 rats were exposed for 8 h (Experiment 1; saturated vapour at room temperature), respectively 6 rats for 4 h (Experiment 2; 10.7 mg/L and 32 mg/L areosol exposure). The post exposure observation period was 14 days. In Experiment 1 no mortality was observed. In Experiment 2 all rats exposed to 32 mg/L died. From the animals exposed to 10.7 mg/L, 2/6 animals died during the course of the study (1955, RL2).

Acute dermal toxicity in rabbits and rats:

Groups of 4 male New Zealand rabbits were dermally exposed to doses of 1.26, 2.5, or 5 mL/kg bw. The post exposure observation period was 14 days. One out of 4, 2/4, or 4/4 rabbits died after exposure, respectively. Local effects like erythema, necrosis, desquamation were recorded (no data about systemic effects). Necropsy of dead animals revealed lung hemorrhage, speckled or pitted kidney surface and blood in peritoneum. Conclusion: The dermal LD50 in male rabbits was 2240 µL/kg bw corresponding to 2100 mg/kg bw (1955, RL2).

The approximate lethal dose in pregnant New Zealand White rabbits was determined. One rabbit per dose level received dermal application (coverage: open) at gestation day 15. The post exposure period was 14 days. Results: In pregnant New Zealand White rabbits the approximate letal dose was 5000 mg/kg bw after dermal exposure (Stula et al., 1977).

The approximate lethal dose was also determined in pregnant Sprague-Dawley rats. One rat per dose level received dermal application (coverage: open) at gestation day 11. The post exposure period was 9 days. Conclusion: In pregnant Sprague-Dawley rats the approximate letal dose was 7500 mg/kg bw after dermal exposure (Stula et al., 1977).

Observations in humans

The odour threshold in the trained panel of four staff members of the Food and Flavour Section was 47 ppm (170 mg/m³); odour description: amine, burnt, oily (see Section 7.12; Leonardos et al., 1969).

Toxic effects including acute delirium/hallucinations, skin burns, cellulitis, conjunctivitis, chemical-induced hepatitis, secondary coagulopathy, esophagitis (grade 2 severity), rhabdomyolysis in a male worker after inhalative and dermal exposure for 90 minutes to a mixture of 0.5% unreacted 1,2-ethanediamine, 34.5% polyurethane, and 65% N,N-dimethylacetamide (Marino et al., 1994; see Section 7.10.3).

Summary of acute toxicity with respect to the derivation of acute DNELs

N,N-Dimethylacetamide is practically non-toxic after acute oral exposure in rats (LD50 ranged between 4800 - 5830 mg/kg bw), mice (LD50: 4610 - 6020 mg/kg bw), and rabbits (LD50: 2820 mg/kg bw). The dog seems to be more sensitive than other species; lethal effects were detected at 470 mg/kg bw (mortality: 0/2 at 235 mg/kg bw, 1/4 at 470 mg/kg bw, 2/2 at 940 mg/kg bw, 1/2 at 1900 mg/kg bw). Clinical signs were refused food consumption, extensor spasm, bleeding of the nose. Death occurred on day 3-4. Clinical chemistry findings and effects on the liver seen at necropsy of the dead animals suggested adverse liver effects; 235 mg/kg bw represented the NOAEL. Overall, the data suggested that the target organ of acute oral toxicity is the liver (dog and rat), stomach (mice, rabbits, rats) and kidney (rats). However, Weiss et al. (1962, see section 7.10.3) reported toxicity but no mortality when doses up to 610 mg/kg bw were given intravenously to tumor patients. This indicates that the acute oral study in the dog rather overestimates the acute lethal potential and should be considered as non-relevant with regard to the classification of DMAC's acute oral toxicity according to Regulation (EC) No 1272/2008. Nevertheless, the NOAEL of 235 mg/kg bw derived from the acute toxicity study in dogs could be taken into consideration for the derivation of an acute/short-term oral DNEL.

 

Inhalation hazard tests revealed no lethal effects in rats after exposure to the saturated vapour generated at room temperature or even at 50°C. In further experiments on acute inhalation toxicity in rats the LC50 (1 h) in female rats was estimated to be 8.8 mg/L (Kennedy, 1986); no mortality was seen in male rats at the time weighted average of 8.8 mg/L (highest concentration used). Extrapolation of this LC50 value to an exposure duration of 4 hours according to Haber's law (Cnx t = K; with n = 1 for extrapolation from shorter to longer exposure duration acc. to ECHA, 2012) leads to an LC50 (4 h) of 2.2 mg/L.

The dermal LD50 in male rabbits is 2100 mg/kg bw (Union Carbide, 1955).

The focus of the available studies on acute inhalation and dermal toxicity was on the determination of mortality rates. They are not sufficient to derive robust NOAECs/NOAELs for acute toxicity.

Reference

ECHA (2012). Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health; Version 2.1.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is considered to be classified for acute inhalation toxicity under Regulation (EC) No. 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.

Furthermore, N,N-Dimethylacetamide is included in Annex VI of Regulation (EC) No. 1272/2008 with the following legal classification:

  • Acute toxicity - dermal Cat. 4 (H312: harmful in contact with skin)
  • Acute toxicity - inhalation Cat 4 (H332: Harmful in inhaled)