1,3-bis(hydroxymethyl)urea

Endpoint summary

Description of key information

Oral:

In an in vivo acute oral toxicity study in rats (Acute-Toxic-Class Method = ATC-Method) according to OECD Guideline 423, a LD50 > 2000 mg/kg bw was determined (UN GHS: No Category) (reference 7.2.1-1).

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:

03 July 2017 to 22 September 2017

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)

Version / remarks:

2002

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI (Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzfeld, Germany
- Age at study initiation: 9 weeks
- Weight at study initiation: 169 g (157 - 173 g)
- Fasting period before study: Diet was withheld from about 17 to 20 hours before start of treatment until 4 hours after administration.
- Housing: group-housed (3 per group) in type IV Makrolon cages, one day before treatment, the rats were single-housed in type III Makrolon cages.
- Diet: maintenance diet (VI534, ssniff Spezialdiaten GmbH. Germany) ad libitum
- Water: Drinking water from the community water supply was offered ad libitum in Makrolon' bottles (BIOSCAPE GmbH, Castrop-Rauxel, Germany). Drinking water was changed at least three times per week.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.0 - 23.3
- Humidity (%): 45.3 - 76.6

Route of administration:

oral: gavage

Vehicle:

other: 0.25% aqueous hydroxypropylcellulose (Methocel K4M Premium solution, 2.5 g/L distilled water)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 g/L
- Justification for choice of vehicle: well tolerated and established standard vehicle

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw


CLASS METHOD
- Rationale for the selection of the starting dose: Due to the chemical properties of the test item, mortality was not expected at the highest starting dose of 2000 mg/kg bw. Therefore, the study was started with 2000 mg/kg bw in three female rats and continued with further three females at 2000 mg/kg bw.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: On the day of treatment, each animal was observed for mortality and for symptoms of intoxication at scheduled intervals according to the record sheets. On the following days, the rats were examined once daily. Symptoms were recorded individually for each animal. All animals were weighed before treatment (day 1) and on day 2, 4, 6, 8, 11, 13 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was seen.

Clinical signs:

No clinical signs of toxicity were observed.

Body weight:

There were no effects on the body weight development throughout the study.

Gross pathology:

No organ alterations were identified during the gross pathological examination.

Interpretation of results:

GHS criteria not met

Conclusions:

In an in vivo acute oral toxicity study in rats (Acute-Toxic-Class Method = ATC-Method) according to OECD Guideline 423, a LD50 > 2000 mg/kg bw was determined.

Executive summary:

In an in vivo acute oral toxicity study in Wistar rats (Acute-Toxic-Class Method = ATC-Method) according to OECD Guideline 423, the acute oral toxicity of N,N`-Bis(hydroxymethyl)urea was determined. The study was started with 2000 mg/kg bw in 3 young adult female rats (Crl:WI (Han)). Since no mortality was observed, the test was continued with further 3 females treated with 2000 mg/kg bw. Mortality and clinical signs were monitored for at least 6 hours after administration and then daily for 14 days. All animals were weighed before treatment (day 1) and on days 2, 4, 6, 8, 11, 13, and 15. At the end of the observation period, all surviving rats were sacrificed and subjected to a detailed necropsy. No mortality occurred during the course of this study. No clinical signs of toxicity were observed. The body weight development was inconspicuous throughout the study. The gross pathological examination revealed no organ alterations. The test substance has no acute toxic potential under the conditions of the present study, and the LD50 value is higher than 2000 mg/kg bw after single oral administration in female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

Guideline conform GLP study.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In an in vivo acute oral toxicity study in Wistar rats (Acute-Toxic-Class Method = ATC-Method) according to OECD Guideline 423, the acute oral toxicity of the test substance was determined (reference 7.2.1 -1). The study was started with 2000 mg/kg bw in 3 young adult female rats (Crl:WI (Han)) and continued with further 3 females treated with 2000 mg/kg bw. Mortality and clinical signs were monitored for at least 6 hours after administration and then daily for 14 days. All animals were weighed before treatment (day 1) and on days 2, 4, 6, 8, 11, 13, and 15. At the end of the observation period, all surviving rats were sacrificed and subjected to a detailed necropsy. No mortality occurred during the course of this study. No clinical signs of toxicity were observed. The body weight development was inconspicuous throughout the study. The gross pathological examination revealed no organ alterations. The test substance has no acute toxic potential under the conditions of the present study, and the LD50 value is higher than 2000 mg/kg bw after single oral administration in female rats.

These findings are supported by a study conducted to evaluate the acute oral toxicity of the test substance in rats (reference 7.2.1-2). The test substance was administered by gavage in doses of 200, 1600, 3200 and 6400 mg/kg bw to 10 animals each. During the observation period of 7 days no mortality occurred in all dose groups and no signs of toxicity were detected. Pathological examinations revealed no changes. The LD50 for acute oral toxicity was established to be > 6400 mg/kg bw in rats.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental data are reliable and suitable for classificatin purposes under Regulation (EC) No 1272/2008. Based on these data, the test item should not be considered to be classified for acute oral toxicity according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.