2-Chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 Feb - 28 Mar 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

adopted in 2001

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

adopted in 2008

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

adopted 2002

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Food and Agricultural Materials Inspection Centre (FAMIC), 12 Nohsan, Notification No. 8147

Version / remarks:

adopted in 2011

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

1

Reference substance name:

2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Cas Number:

1211443-61-6

Molecular formula:

C14 H17 Cl N4 O

IUPAC Name:

2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Test animals

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 Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8 or 9 weeks
- Fasting period before study: animals were fasted overnight and until 3 - 4 h after administration
- Housing: 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum (analysis were performed)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 40 - 70
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration vehicle: 1% aqueous carboxymethyl cellulose
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at WIL Research Europe and on test substance data supplied by the sponsor.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

2000 mg/kg bw
300 mg/kg bw

No. of animals per sex per dose:

3 females per step (4 steps)

Control animals:

no

Remarks:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15 clinical signs were recorded. The symptoms were graded according to fixed scales and the time of onset, degree and duration was recorded. Mortality/Viability was recorded twice daily. The time of death was recorded as precisely as possible.
- Necropsy of survivors performed: yes

Statistics:

Mean values and standard deviations were calculated for body weights.

Results and discussion

Effect levels

Effect levels 1

Sex:

female

Dose descriptor:

LD50 cut-off

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Step 1: At 2000 mg/kg bw, 1 of 3 animals was sacrificed for humane reasons on Day 2.
Step 2: At 2000 mg/kg bw, all 3 animals were found dead on Day 2.
Step 3+4: At 300 mg/kg bw, no mortality occurred during the study period.

Clinical signs:

other: At 2000 mg/kg bw, lethargy, flat posture, hunched posture, lateral recumbency, uncoordinated movements, piloerection, chromodacryorrhoea, clonic spasms, quick breathing and/or watery discharge from the eye were noted for the animals. The surviving animals

Gross pathology:

At 2000 mg/kg bw, abnormalities of the body cavities (thoracic cavity, diaphragm: dark red, hard, nodule 8x6 mm), small intestines (contents: black discolouration), caecum (contents: black, hard) and/or emaciation were found in the animals that died or were sacrificed for humane reasons during the study, at macroscopic post mortem examination. Macroscopic examination of the surviving animals at
termination did not reveal any abnormalities.
At 300 mg/kg bw, abnormalities of the left kidney (enlarged, contents: watery-clear), ureter (left side: dilation) and/or thymus (isolated, reddish focus/foci) were found in two animals, at macroscopic examination. Macroscopic examination of the other animals at termination did not reveal any abnormalities.

Any other information on results incl. tables

Table 1: Absolute body weights

Starting dose (mg/kg bw)	Animal No.	Body weight (g)
		Day 1	Day 8	Day 15
2000	1	152	177	198
	2	148	171	189
	3	135	*	-
	Mean ± SD	145 ± 9	174 ± 4	194 ± 6
	4	181	**	-
	5	168	**	-
	6	175	**	-
	Mean ± SD	175 ± 7	-	-
300	7	181	209	214
	8	197	230	241
	9	177	206	210
	Mean ± SD	185 ± 11	215 ± 13	222 ± 17
	10	162	188	195
	11	172	188	212
	12	160	189	194
	Mean ± SD	165 ± 6	188 ± 1	200 ± 10

* Animal sacrificed for humane reasons on Day 2, bodyweight at death 125 g

** Animals found dead on Day 2, body weights at death 171 g, 157 g and 167 g, respectively

Applicant's summary and conclusion

Interpretation of results:

other: CLP/EU GHS Category 4 (H302) according to Regulation (EC) No 1272/2008

Conclusions:

CLP: Acute Oral 4, H302

An acute oral toxicity study according to OECD Guideline 423 in rats was performed with the test substance and resulted in a LD50 between 300 and 2000 mg/kg bw. Thus the test substance does meet the classification criteria according to Regulation (EC) 1272/2008.