Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrahydro-1,3-dimethyl-1H-pyrimidin-2-one
EC Number:
230-625-6
EC Name:
Tetrahydro-1,3-dimethyl-1H-pyrimidin-2-one
Cas Number:
7226-23-5
Molecular formula:
C6H12N2O
IUPAC Name:
tetrahydro-1,3-dimethyl-1H-pyrimidin-2-one
Test material form:
other: liquid
Details on test material:
- Name of test item: N,N'-Dimethyl propylene urea
- Batch identification: B 1263 vom 07.09.2011
- CAS No.: 7226-23-5
- Physical state/ color: Liquid / colorless, clear
- Purity: 99.6 g/100 g determined by 1H-NMR analysis
- Homogeneity: The test item was homogeneous by visual inspection.
- Storage stability: The stability of the test item under storage conditions over the study period was guaranteed by the sponsor.
- Storage conditions: Refrigerator
- Density [g/mL]: 1.065 (determined by Bioassay)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzfeld, Germany
- Age at study initiation: Young adult animals (male animals approx. 8 weeks, female animals approx. 12 weeks)
- Weight at study initiation: Animals of comparable weight (mean ± SD: males, 2000 mg/kg group: 242 ± 12 g; females, 2000 mg/kg group: 209 ± 4 g; males, 1000 mg/kg group: 234 ± 9 g; females, 1000 mg/kg group: 209 ± 8 g)
- Housing: single housing in Makrolon cages, type III
- Diet: VRF1(P) (SDS Special Diets Services, Altrip, Germany)
- Water: Tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12 (6.00 p.m. - 6.00 a.m. / 6.00 a.m. - 6.00 p.m.)

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: about 40 cm²
- % coverage: at least 10% of the body surface
- Type of wrap if used: an air-permeable dressing (4 layers of absorbent gauze (Ph. Eur. supplied by Lohmann GmbH & Co., KG) and stretch bandage (Fixomull Stretch (adhesive fleece) supplied by Beiersdorf AG)

REMOVAL OF TEST SUBSTANCE
- Washing: rinsing of the application site with warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount applied: 2000 mg/kg bw group: 1.88 mL/kg bw; 1000 mg/kg bw group: 0.94 mL/kg bw
- Concentration: undiluted
Duration of exposure:
24 hours
Doses:
2000 and 1000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: A check for any dead or moribund animals was made at least once each workday. Recording of clinical signs several times on the day of administration, and at least once daily thereafter each workday for the individual animals. Individual body weights were determined shortly before administration (day 0), weekly thereafter and on the last day of observation; additionally, at day of death in animals that died starting with study day 1.
- Necropsy of survivors performed: yes
- Other examinations performed: Scoring of skin findings (assessment according to Draize; individual readings 30 – 60 minutes after removal of the semi-occlusive dressing (day 1), several times until the last day of observation).

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Three female animals died in the 2000 mg/kg dose group. No mortality occurred in the 1000 mg/kg dose group.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality.
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Three female animals died in the 2000 mg/kg dose group.
Mortality:
Three female animals died in the 2000 mg/kg dose group 1 or 2 days after application. No mortality occurred in the 1000 mg/kg dose group.
Clinical signs:
other: Male animals: Impaired general state and dyspnoea were observed from study day 1 until study day 9 in all male animals of the 2000 mg/kg test group. Additionally piloerection was noted in these animals from study day 1 or 2 until study day 9 after applica
Gross pathology:
In the female animal which were found dead on study day 1 the following macroscopic pathologic findings were observed: Light red spotted discoloration of the liver, all lobes fine spotted, extensive bleeding in the glandular stomach, yellowish discoloration of the small intestine- and stomach content and red discoloration of the small intestine.
Macroscopic pathologic abnormalities like dark red, spotted discoloration of all lung lobes, marginal dark discoloration and beige discoloration of the central part of the liver, red discoloration of the small intestine content, petechial bleeding in the glandular stomach and red discoloration of the small intestine were seen in the animals which were found dead on study day 2.
No macroscopic pathologic abnormalities were noted in the animals examined on the last day of observation (2000 mg/kg: 5 males and 2 females; 1000 mg/kg: (5 males and 5 females)).
Other findings:
Local effects: Male animals: No local effects were observed in the 2000 and 1000 mg/kg test groups. Female animals: In the 2000 mg/kg test group skin effects of the two surviving animals were well- defined erythema (grade 2) and scaling. These effects were noted from study day 2 until study day 9 after application. In the 1000 mg/kg test group very slight erythema (grade 1) was noted on study day 2 and 3 in one animal. In two further animals well-defined erythema (grade 2) was noted from study day 1 or 2 until study day 3. In one of these animals well-defined erythema decreased to very slight erythema on study day 6 and was noted again on study day 7 and 8. Incrustations were noted in two animals from study day 2 or 6 and persisted until study day 8.

Applicant's summary and conclusion

Interpretation of results:
sligthly toxic
Remarks:
Migrated information
Conclusions:
Under the conditions of this study the median lethal dose (LD50) of N,N'-Dimethyl propylene urea after dermal application was found to be greater than 2000 mg/kg bw in male and female rats.
Executive summary:

The study was performed according to OECD guideline 402 in compliance with GLP.

 

In this acute dermal toxicity study, young adult Wistar rats (5 animals per sex per dose) were dermally exposed to two doses of 2000 and 1000 mg/kg bw of the undiluted test item N,N'-Dimethyl propylene urea to the clipped skin (dorsal and dorso-lateral parts of the trunk) and covered by semi-occlusive dressing for 24 hours. The application area comprised at least 10% of the total body surface area. The animals were observed for 14 days.

 

2000 mg/kg test group:

No male animals died. Three female animals died.

The following test item-related clinical observations were recorded during the course of the study:

Male animals: Impaired general state, dyspnea, piloerection, reduced feces in one animal, chromodacryorrhea.

Female animals: Impaired general state, poor general state, dyspnea, piloerection, abdominal position, staggering, tremor, chromodacryorrhea, exsiccosis.

The following test item-related local effects were recorded during the course of the study:

No local effects were noted in all male animals, erythema grade 2 in two females, scaling in two females.

The following macroscopic pathologic abnormalities were recorded in the female animals that died:

Dark red, spotted discoloration of all lobes of lung, marginal dark discoloration and beige discoloration of the central part of the liver, light red spotted discoloration of the liver, all lobes fine spotted, yellowish discoloration of the stomach content, extensive or petechial bleeding in the glandular stomach, red discoloration of the small intestine, red or yellowish discoloration of the small intestine content. No pathologic findings in the animals sacrificed at the end of the observation period (5 males and 2 females).

The mean body weights of the male and surviving female animals decreased during the first post-exposure observation week but increased during the second week within the normal range.

 

1000 mg/kg test group:

No mortality occurred.

The following test item-related clinical observations were recorded during the course of study:

Male animals: Impaired general state in two animals, dyspnoea in two animals, piloerection in two animals.

Female animals: Impaired general state in one animal, dyspnoea in one animal, piloerection in one animal.

The following test item-related local effects were recorded during the course of study:

No local effects were noted in all male animals, erythema grade 1 and 2 in 3 females, incrustations in 2 females.

The mean body weight of the male animals increased within the normal range throughout the study period. The mean body weight of the female animals did not adequately increase during the first post-exposure observation week, but increased during the second week.

No macroscopic pathologic abnormalities were noted in the animals examined at the end of the study (5 males and 5 females).

 

Conclusion: The acute dermal median lethal dose (LD50) was determined to be

LD50, dermal, rat, males > 2000 mg/kg bw

LD50, dermal, rat, females approx. 2000 mg/kg bw

LD50, dermal, rat, males and females > 2000 mg/kg bw

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