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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28th September 2017 to 20th October 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: EPA Health Effects Test Guidelines, the Consumer Product Safety Commission (CPSC) issued pursuant to and for the implementation of the Federal Hazardous Substances Act, 16 CFR Part 1500.3(c)(2)(i)(A),
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
5-[4-Methoxy-2-(propan-2-yl)phenoxy]pyrimidine-2,4-diamine
Cas Number:
865304-71-8
Molecular formula:
C14H18N4O2
IUPAC Name:
5-[4-Methoxy-2-(propan-2-yl)phenoxy]pyrimidine-2,4-diamine
Test material form:
solid: crystalline
Details on test material:

Off-white
Specific details on test material used for the study:
known as y: L-001739764-000M020 in reports

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
Animals were received from Charles River, Stone Ridge NY on 12 Sep 2017 and 19 Sep 2017. Following an acclimation period of at least five days, five healthy, non-pregnant and nulliparous female Sprague Dawley rats were selected for dosing without conscious bias.
The animals were born on 17 Jul 2017 and 24 Jul 2017. The pretest body weight range was 193 - 229 grams. The weight variation of the animals used did not exceed ± 20% of the mean weight of the previously dosed animals.
The animals were identified by cage notation and indelible body marks, and individually housed in suspended wire-bottom cages. Absorbent paper bedding was placed beneath the cages and changed at least three times per week. Fresh PMI Rat Chow (Diet No. 5012) was freely available except for 16 to 20 hours prior to dosing. Water was available ad libitum. The animal room, reserved exclusively for rats on acute tests, was temperature controlled, had a 12-hour light/dark cycle, and was kept clean and vermin free.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The test article was mixed with distilled water to make dosing by gavage possible. The dose was based on the dry weight of the test article. Initially, a single female Sprague Dawley rat was dosed orally by syringe and dosing needle at a dose level of 2000 mg/kg. Since the animal survived, four additional females were dosed at 2000 mg/kg.
Doses:
One dose of 2000 mg/kg.
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
Observations
In Vivo - 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. 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 termination.
Post Mortem – All animals were humanely euthanized using CO2 following study termination and examined for gross pathology.
Statistics:
Limit Test: An estimate of the LD50 was made based on mortality occurring during the study.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable
Mortality:
None
Clinical signs:
No abnormal physical signs were observed among four animals. Diarrhea was observed 1 and 2 hours following dose administration of one animal.
Body weight:
All five animals gained body weight by study termination.
Gross pathology:
The gross necropsy revealed no observable abnormalities.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 of L-001739764-000M020 is greater than 2000 mg/kg of body weight in female rats.
Executive summary:

Initially, a single female Sprague Dawley rat was dosed orally with L-001739764-000M020 at a dose level of 2000 mg/kg. Since the animal survived, four additional females were dosed at 2000 mg/kg. The rats were observed at 15 minutes, 1, 2 and 4 hours post-dosing and once daily thereafter for 14 days for toxicity and pharmacological effects. All animals were observed twice daily for mortality on Day 1 to Day 14. Body weights were recorded pre-test, weekly and at termination. All animals were examined for gross pathology. The potential for toxicity was based on the mortality response noted.


All five female rats survived following a single oral dose of 2000 mg/kg.
No abnormal physical signs were observed among four animals. Diarrhea was observed 1 and 2 hours following dose administration of one animal. All five animals gained body weight by study termination.
The gross necropsy revealed no observable abnormalities.