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Description of key information

The acute toxic effects of 1,1 -Dimethylurea were investigated after a single peroral administration to rats. The study was performed according to OEDC Guideline 423.

1,1 -Dimethylurea was administered once as solution in deionised water, given orally via gavage to female rats. The dosing was performed sequentially to groups of 3 animals per step using a starting dose of 300 mg per kg body weight and 2000 mg per kg body weight as the second dose.

No toxic effects of the test substance 1,1-Dimethylurea were noted by signs in life and post mortem. No mortality occured. According to the decision tree of the OECD-Guideline 423 theLD50 oral is estimated to be higher than 2000 mg/kg body weight in rats.

According to the results of a preliminary experiment it is impossible to perform an inhalation test with 1,1-Dimethylurea as the substance cannot be generated to dust due to the high hygroscopicity. Furthermore a aqueous solution of 1,1-Dimethylurea failed to be atomized because of uncontrolled bulk crystallization. Because of this two reasonsan acute inhalation study is technically not feasible.

A study was performed to assess the acute dermal toxicity of1,1 -DimethylureainSprague Dawley rats. The method was designed to meettheOECD Guideline for Testing of Chemicals:Acute Dermal Toxicity(No.402, adopted 1987).

A limit test at one dose level of 2000 mg/kg body weight was carried outin a group of 10 animals (5 males and 5 females).

There were no death or moribund animals during the test andno abnormal findings in all animals after dosing from the first day until the end of the test. Also there were no signs of dermal irritation orabnormalities found at necropsy.

Based on the results, the acute dermal LD50in rats for 1,1-dimethylurea was as follows:Male rats:>2000 mg/kg b.w.;Female rats:>2000 mg/kg b.w.

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:
May - July 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
- Analytical purity: at least 98 %
- Impurities (identity and concentrations): max. 2 % Urea, max. 0.2 % Isopropanol, max. 0.5 % diethyleneglycolmonoethylether
- Lot/batch No.: KG 03-13
Species:
rat
Strain:
Crj: CD(SD)
Remarks:
Crl:CD(SD)IGS BR
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH, 97633 Sulzfeld, Germany.
- Age at study initiation: approx. 8 weeks at the time of administration
- Weight at study initiation: 184 - 202 g
- Housing: Single caging in Makrolon cages type III (39 cm x 23 cm bottom area, 18 cm height). Wire mesh lids. Sanitation of cages once a week.
- Diet (e.g. ad libitum): Altromin 1324 forte, gamma irradiated with 25 kGy 60Co, ad libitum (Producer: Altromin GmbH, 32791 Lage, Germany). The feed was withdrawn the evening before the administration of the test substance and was offered again about three hours afterwards.
- Water (e.g. ad libitum): Tap water from an automatic watering system, ad libitum.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Average of 21.9 °C (continuous control and recording)
- Humidity (%): Average of 66.5 % (continuous control and recording)
- Photoperiod (hrs dark / hrs light): Artificial light from 6 a.m. to 6 p.m.
- Air exchanges: 12 per hour
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle: The test substance was enough soluble in water and water shall be used preferably, according to the guideline.

MAXIMUM DOSE VOLUME APPLIED:
10mL per kg body weight
Doses:
1st and 2nd step: 300 mg/kg bw
3rd and 4th step: 2000 mg/kg bw
No. of animals per sex per dose:
3 animals per step and 6 animals per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

Clinical observations:
Observations were performed within the periods 0 - 0.5, 0.5 - 1, 1 - 2, 2 - 4 and 4 - 6 hours after administration (p.a.) of the test substance and then at least once a day for a total of 2 weeks. Observations included but were not limited to changes in skin, fur, eyes, the occurence of secretions and excretions, autonomic activity, changes in gait, posture and the presence of convulsions.

Body weights and body weight gain:
Body weights were determined before administration, 7 days p.a., 14 days p.a.
Body weight gain was calculated for each week of the study, i.e. between 0 and 7 days p.a. and 7 and 14 days p.a.

Necropsy:
The animals were killed by inhalation of 80 % CO2 + 20 % air 14 days p.a. and subjected to a necropsy including a gross pathological examination.
Statistics:
no data
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals survived until the scheduled termination of the study.
Clinical signs:
All animals were normal during the entire observation period.
Body weight:
All animals gained weight in both weeks p.a.
Interpretation of results:
GHS criteria not met
Conclusions:
No toxic effects of the test substance 1,1-Dimethylurea were noted by signs in life and post mortem. No mortality occured. According to the decision tree of the OECD-Guideline 423 the LD50 oral is estimated to be higher than 2000 mg/kg body weight in rats.
Executive summary:

The acute toxic effects of 1,1 -Dimethylurea were investigated after a single peroral administration to rats. The study was performed according to OEDC Guideline 423.

1,1 -Dimethylurea was administered once as solution in deionised water, given orally via gavage to female rats. The dosing was performed sequentially to groups of 3 animals per step using a starting dose of 300 mg per kg body weight and 2000 mg per kg body weight as the second dose. The dose volume was 10 mL per kg body weight for all groups. Observations were performed within the periods 0 - 0.5, 0.5 - 1, 1 - 2, 2 - 4 and 4 - 6 hours after administration (p.a.) of the test substance and then at least once a day for a total of 2 weeks. Observations included but were not limited to changes in skin, fur, eyes, the occurence of secretions and excretions, autonomic activity, changes in gait, posture and the presence of convulsions. Body weights were determined before administration, 7 days p.a., 14 days p.a. Body weight gain was calculated for each week of the study, i.e. between 0 and 7 days p.a. and 7 and 14 days p.a. The animals were killed by inhalation of 80 % CO2 + 20 % air 14 days p.a. and subjected to a necropsy including a gross pathological examination.

No toxic effects of the test substance 1,1-Dimethylurea were noted by signs in life and post mortem. No mortality occured. According to the decision tree of the OECD-Guideline 423 the LD50 oral is estimated to be higher than 2000 mg/kg body weight in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
According to the results of a preliminary experiment it is impossible to perform an inhalation test with 1,1-Dimethylurea as the substance cannot be generated to dust due to the high hygroscopicity. Furthermore a aqueous solution of 1,1-Dimethylurea failed to be atomized because of uncontrolled bulk crystallization. Because of this two reasons an acute inhalation study is technically not feasible.

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:
April - May 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): 1,1-dimethylurea
- Physical state: solid
- Analytical purity: 99.9 %
- Lot/batch No.: 301601
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BeiJing Vital River Laboratory Animal Technology Co., Ltd.
- Age at study initiation: 49-62 days on arrival, in the range of 8-12 weeks at the commencement of each animal’s dosing.
- Weight at study initiation: Males: 261-298 g,Females: 235-261 g, and weight variation was not exceed ± 20% of the mean body weight at grouping.
- Housing: Animals were raised in suspended, stainless steel cages (L 32.0 cm × W 28.0 cm × H 20.0 cm) on cage racks (L 167.0 cm × W 70.0 cm × H 171.0 cm). There were 10 cages per layer, and 4 layers per rack. Animals were housed individually during the test.
- Diet (e.g. ad libitum): Animals were provided with sterilized diet with complete nutrition supplied by Beijing keaoxieli Feed Co., Ltd. (Product License No: SCXK(jing) 2012-0001, Batch NO. 14013213); ad libitum
- Water (e.g. ad libitum): Water was purified by HT-R01000 purity system. Water analysis was conducted routinely analyzed (annually), and all parameters except pH were within the permitted limits described in the national drinking water standard (GB5749-2006) and pH was within the permitted limits described in the purified water standard (GB17324-2003); ad libitum
- Acclimation period: 8 days prior to the test

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0-23.7℃
- Humidity (%): 40%-63%
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorsal Area of the trunk
- coverage: 5 cm x 5.5 cm
- Type of wrap if used: white medical tape (non-irritating)

REMOVAL OF TEST SUBSTANCE
At the end of the exposure period for approximated 24 hours, residual test item was removed by using water

:
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
five males and five females
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual weights of animals were determined at grouping, on Day 0 (day of dosing), Day 7 and 14. Changes in weight were calculated and recorded.
- Necropsy of survivors performed: yes
Clinical observations were performed once during the first 30 min, and at 1, 2 and 4 hours after application and then once each day for 14 days.
Careful observation and record of animal fur changes, eyes and mucosa, respiratory, circulatory, autonomic and central nervous system, particularly limb activity and behavior change was made.
Particular attention was directed to observations of tremors, convulsions, salivation, diarrhea, lethargy, sleep and coma.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no death or moribund animals during the test.
Clinical signs:
There were no abnormal findings in all animals after dosing from the first day until the end of the test.
Body weight:
Only one animal showed a very small decrease of body weight during the first week. But overall also this animal showed growth during the whole observation period.The results indicated that the body weight gain of all animals showed growth.
Gross pathology:
No abnormalities were found at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results, the acute dermal LD50 in rats for 1,1-dimethylurea was as follows:
Male rats: > 2000 mg/kg b.w.
Female rats: > 2000 mg/kg b.w.
Executive summary:

A study was performed to assess the acute dermal toxicity of 1,1 -Dimethylurea in Sprague Dawley rats. The method was designed to meet the OECD Guideline for Testing of Chemicals: Acute Dermal Toxicity (No.402, adopted 1987).

A limit test at one dose level of 2000 mg/kg body weight was carried out in a group of 10 animals (5 males and 5 females). Clinical observations were made once during the first 30 min, and at 1, 2 and 4 hours after dosing and then once each day for up to 14 days. Individual weights of animals were determined at grouping, before dosing (Day 0), on day 7 and 14. At the end of the test, a gross necropsy was performed on all test animals.

There were no death or moribund animals during the test and no abnormal findings in all animals after dosing from the first day until the end of the test. Also there were no signs of dermal irritation or abnormalities found at necropsy.

Based on the results, the acute dermal LD50in rats for 1,1-dimethylurea was as follows:

Male rats:>2000 mg/kg b.w.

Female rats:>2000 mg/kg b.w.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for classification or non-classification

The acute toxic effect of 1,1 -Dimethylurea was assessed in an acute oral toxicity test according to OECD 423 and in an acute dermal toxicity test according to OECD 402. No toxic effects of the test substance 1,1 -Dimethylurea were noted and no mortality occured up to the highest dose of 2000 mg/kg bw. Therefore 1,1 -Dimethylurea does not have to be classified as acute toxic.