4-chloro-7H-pyrrolo[2,3-d]pyrimidine

Endpoint summary

Description of key information

The acute oral toxicity is performed using up and down procedure according to OECD Guideline 425 under GLP.

The estimated oral LD50 and 95% confidence limits of the test item is 1161 (550 to 2000) mg/kg of body weight in female rats.

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:

From 20 Dec 2016 to 01 Feb 2017

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Rationale for alternative/additional species to rat (if applicable)
- Source: Charles River, Raleigh NC, Stone Ridge NY and St. Constant Quebec
Canada
- Females (if applicable) nulliparous and non-pregnant: yes
- Rationale for use of males (if applicable)
- Age at study initiation: 8 weeks
- Weight at study initiation: The pre-test body weight range was 193 - 279 grams.
- Fasting period before study: yes, 16-20 hours prior to dosing.
- Housing: The animals were individually housed in suspended wire-bottom cages. Absorbent paper bedding was placed beneath the cages and changed at least three times per week.
- Historical data:
- Diet (e.g. ad libitum): Fresh PMI Rat Chow (Diet No.5012) was available ad libitum except for 16-20 hours prior to dosing.
- Water (e.g. ad libitum): Water was available ad libitum.
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Route of administration:

oral: gavage

Vehicle:

water

Doses:

550, 2000, 4000 mg/kg

No. of animals per sex per dose:

2000 mg/kg (two females) and 4000 mg/kg (one female)
550 mg/kg: 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed at 15 minutes, 1, 2 and 4 hours post-dosing and once daily thereafter for 14 days for toxicity and pharmacological effects.
- Necropsy of survivors performed: All animals were humanely euthanized using CO2 following study termination and examined for gross pathology.
- Clinical signs including body weight: Observations included, but were not limited to, evaluation
of skin and fur, eyes and mucous membranes, respiratory and circulatory effects, autonomic effects such as salivation, central nervous system effects including tremors and convulsions, changes in the level of activity, gait and posture, reactivity to handling or sensory stimuli, altered strength, and stereotypies or bizarre behavior (e.g., self-mutilation, walking backwards). All animals were observed twice daily for mortality on Day 1 to Day 14. Body weights were recorded pre-test, weekly, and at death or termination in the survivors.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1 161 mg/kg bw

Based on:

test mat.

95% CL:

> 550 - < 2 000

Mortality:

Three female rats died, by Day 1, following a single 2000 mg/kg (two animals) and 4000 mg/kg (one animal) oral dose.
Three female rats survived following a single 550 mg/kg oral dose.

Clinical signs:

other: Dose Level: 2000 and 4000 mg/kg Prior to death, abnormal physical signs including piloerection, wetness of the nose/mouth area, lacrimation, chromorhinorrhea, lethargy, tremors, flaccid muscle tone, negative righting reflex, prostration, closed eyes, chro

Gross pathology:

Dose Level: 2000 and 4000 mg/kg
The gross necropsy revealed red staining of the nose/mouth area, wetness and brown and gray staining of the anogenital area, darker than normal lungs, excess fluid in the pleural cavity, abnormalities of the gastrointestinal tract, distention of the stomach (white fluid), pale areas on the liver and red fluid in the bladder.
Dose Level: 550 mg/kg
The gross necropsy of the survivors revealed no observable abnormalities.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The estimated oral LD50 and 95% confidence limits of the test item is 1161 (550 to 2000) mg/kg
of body weight in female rats.

Executive summary:

The acute oral toxicity is performed using up and down procedure according to OECD Guideline 425 under GLP.

The estimated oral LD50 and 95% confidence limits of the test item is 1161 (550 to 2000) mg/kg of body weight in female rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 161 mg/kg bw

Quality of whole database:

reliable without restriction

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Acute toxicity:

Oral, OECD 425: LD50 = 1161 (550 to 2,000) mg/kg body weight

Therefore in accordance with Regulation (EC) No. 1272/2008 (amended by 286/2011) Table 3.1.1, this substance should be classified as Category 4.

 

Specific target organ toxicity-single exposure:

Oral:

For the died animals, the gross necropsy revealed red staining of the nose/mouth area, wetness and brown and gray staining of the anogenital area, darker than normal lungs, excess fluid in the pleural cavity, abnormalities of the gastrointestinal tract, distention of the stomach (white fluid), pale areas on the liver and red fluid in the bladder.

No abnormalities were noted at necropsy in survived animals.

As there were no effects considered to support classification for Category 1 and 2 observed. Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.8.1 and 3.8.2, this substance should not be classified.