Tetrahydro-1,3-dimethyl-1H-pyrimidin-2-one

Endpoint summary

Description of key information

LD50 (oral, rat) = 1770 mg/kg bw (BASF SE, 1989; OECD 401)
LD50 (dermal, rat, male/female) > 2000 mg/kg bw (BASF SE/Bioassay, 2012; OECD 402)

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well-documented, guideline-conform study report

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Five animals per cage were housed in stainless steel wire mesh cages. The animals were held in fully air-conditioned rooms with a central air conditioning in a range of 20 - 24°C and a relative humidity between 30 - 70%. The day/night rhythm was 12 h light and 12 h dark. The rats were identified using cage cards. A standardized rat feed diet and tap water were available ad libitum. The animals were given no feed about 16 h before administration; water was available ad libitum.

Route of administration:

oral: gavage

Vehicle:

water

Doses:

681, 1470, 2000 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
Recording of signs and symptoms were done several times on the day of administration (at least once each working day). A check for moribund and dead rats were made twice each working day and once on public holidays.
Withdrawal of food about 15 hours before sacrifice with CO2; necropsy with gross-pathological examination. Necropsy was done of all a nimals that die as early as possible.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 770 mg/kg bw

Based on:

test mat.

Mortality:

Male animals: 681 and 1470 mg/kg: no mortalities after 14 days. 2000 mg/kg: 4/5 after 14 days.
Female animals: 681 mg/kg: no moralities after 14 days. 1470 mg/kg: 1/5 after 14 days. 2000 mg/kg: 4/5 after 14 days.

Clinical signs:

other: Dyspnea, apathy, staggering, twitching, piloerrection, cyanosis (males only), impaired general state (females only) poor general state.

Gross pathology:

Animals that died: general congestion; lungs: intensified hyperemia in few animals.
Sacrificed animals: nothing abnormal detected.

Interpretation of results:

moderately toxic

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 770 mg/kg bw

Quality of whole database:

Well-documented, guideline-conform study report with Klimisch score 2.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP 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:

no

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.)

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).

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.

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

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

GLP guideline study with Klimisch score 1.

Additional information

Acute oral toxicity:

The acute oral toxicity of the test item was evaluated in rats according to OECD 401 guidelines. The test item (dissolved in water) was administered by oral route (gavage) to three groups of five fasted female and male Wistar rats at the dose-levels of 2000, 1470 and 681 mg/kg bw under a dose-volume of 10 mL/kg. Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test item. All animals were subjected to necropsy.

No mortality was noted up to 14 day following application of the test item in males receiving doses of 681 and 1470 mg/kg and in females receiving 681 mg/kg; however, at the dose-level of 1470 mg/kg, 1/5 females died and at dose levels of 2000 mg/kg, 4/5 males and females died within 14 days following test item administration.

The body weight of mals rats was 170 -181 g at the beginning of the study and 237 - 271 g after 13 days; the body weight of females was 179 - 188 g at the beginning and 207 - 222 g after 13 days. Clinical signs observed during the study included dyspnea, apathy, staggering, twitching, piloerrection, cyanosis (males only) and an impaired general state (females only) state. Sacrificed animals surviving the treatment did not show any pathological signs; signs of general congestion and intensified hyperemia in the lungs were noted in animals that died.

Under the experimental conditions of this study, the oral LD50 of the test item was calculated as 1770 mg/kg.

Acute dermal toxicity:

The acute dermal toxicity of the test item was evaluated in rats according to OECD 402 guidelines and GLP. 2000 and 1000 mg/kg of the test item were applied to about 40 cm² of the skin of of ten Wistar rats (five males and five females). The test site was then covered by a semi-occlusive dressing for 24 hrs and animals monitored for 14 days.

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 in both sexes.

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 application. On study day 1, chromodacryorrhea was noted in 4 males. Reduced feces was noted on study day 8 and 9 in one animal. Furthermore, two male animals of the 1000 mg/kg test group showed impaired general state, dyspnoea and piloerection on study day 2 and 3. However, no local effects were observed in the 2000 and 1000 mg/kg test groups. Taken together, the dermal LD50 in male rats is > 2000 mg/kg.

Female animals:

In female animals, one of the two surviving animals in the 2000 mg/kg test group showed poor general state on study day 1 up to study day 2 after application and changed to impaired general state from study day 5 until day 9. Additionally piloerection and dyspnoea were observed in this animal from day 1 or 2 up to day 9, wile exsiccosis was noted from study day 2 until study day 7, tremor on day 1 and 2 and staggering and chromodacryorrhea only on the first day after administration. The second surviving animal showed impaired general state, piloerection and dyspnoea from study day 1 until day 12. Additionally exsiccosis was noted from study day 2 until study day 12, wile chromodacryorrhea was noted on day 1 and 2 after administration. The three animals that died showed poor or impaired general state, chromodacryorrhea, tremor and dyspnoea. In two of them additionally abdominal position was observed. Because of mortality all signs were only observed on study day 1 after administration. Only one female animal of the 1000 mg/kg test group showed impaired general state, dyspnoea and piloerection on study day 2 and 3. 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.

The mean body weights of the male and the surviving female animals in the 2000 mg/kg decreased during the first post-exposure observation week but increased during the second week within the normal range. The mean body weight of the male animals in the 1000 mg/kg test group increased within the normal range throughout the study period. The mean body weight of the female animals did not increase during the first postexposure observation week, but increased during the second week.

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, yellow 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)). Taken together, the dermal LD50 in female rats is ca. 2000 mg/kg.

Under the experimental conditions of this study, the dermal LD50 of the test item was higher than 2000 mg/kg in male and female rats.

Justification for selection of acute toxicity – inhalation endpoint
In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted as two other routes are provided.

Justification for classification or non-classification

According to Directive 67/548/EEC, Annex I and based on the available acute oral toxicity study, the following harmonised classificaton and labelling of the substance is proposed: Xn, R22 "harmful if swallowed". According to Regulation (EC) No 1272/2008 CLP), Annex VI, the substance is classified as category 4 and labelled with "Warning" and H302.

Based on the available acute dermal toxicity study, no classification and labeling is required for the dermal route (according to Directive 67/548/EEC and according to CLP).