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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 April 2018 - 31 May 2018
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:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Method B1 bis of Council Regulation (EC) No 440/2008
Deviations:
not specified
GLP compliance:
yes
Remarks:
including Compliance Statement and signatur page
Test type:
fixed dose procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
5-(Methylsulfonyl)pyridine-2-carbonitrile
EC Number:
682-451-9
Cas Number:
848141-13-9
Molecular formula:
C7 H6 N2 O2 S
IUPAC Name:
5-(Methylsulfonyl)pyridine-2-carbonitrile
Test material form:
solid

Test animals

Species:
rat
Strain:
other: Crl:WI(Han)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Female (nulliparous, non-pregnant) Crl:WI(Han) strain rats were obtained from Charles
River (UK) Ltd., Margate
- The rats were in a body weight range of 141 to 196 g on Day 1.
- Rats were approximately 8 to 10 weeks old on Day 1.

CONDIDITIONS
- Mains water was provided ad libitum via water bottles
- Animals had access to 5LF2 EU Rodent Diet 14%, which was freely
available to the animals at all times, except for a period of fasting from the evening of the day
prior to dosing (Day-1) until approximately 3 hours after dosing.
- The animal rooms were designed to permit 15 to 20 air changes per hour. The target
temperature and humidity ranges were 20 to 24°C and 45 to 65% respectively.
- Fluorescent lighting was controlled automatically to give a cycle of 12 hours light and
12 hours dark.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
1% w/v at a dose volume of 10mL/kg
Details on oral exposure:
Doses were administered orally, by gavage, using plastic syringes and rubber catheters. Each
rat was dosed once on Day 1, by passing the tip of a catheter along the oesophagus and
instilling the test article into the gastric lumen.
Doses:
300 mg/kg bw (sighting study only)

2000 mg/kg bw
No. of animals per sex per dose:
1 female per 300 mg/kg bw (sighting study)
1 female per 2000 mg/kg bw (sighting study)
3 females per 2000mg/kg bw (main study)
Control animals:
no
Details on study design:
All animals were observed at the beginning and the end of the working day for signs of ill
health or overt toxicity.

Treated rats were observed closely for clinical signs of reaction to treatment. Clinical signs
were recorded immediately post-dose, at approximately 15 and 30 minutes post-dose, hourly
between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3 and 4 and once daily
from the fifth to last day of the observation period. Individual records of clinical signs were
maintained for each treated rat.

Rats were weighed on Day-1 (day before dosing) and on Days 1, 4, 8 and 15.

Results and discussion

Preliminary study:
In the preliminary study female fasted rats were given the test article as a single dose on
Day 1 by oral gavage at dose levels of 300 and 2000 mg/kg.
Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
< 2 000 mg/kg bw
Mortality:
There were no deaths at 300 mg/kg.
One animal treated at 2000 mg/kg was found dead on Day 2 and one animal was humanely
killed due to the severity of the clinical signs on Day 8.
Clinical signs:
No clinical signs were observed in animals treated at 300 mg/kg.

Chromodacryorrhea, thin appearance, decreased activity, hunched posture, anogenital soiling
and piloerection were noted in the animals dosed at 2000 mg/kg. The clinical signs developed
one day after dosing and lasted up to Day 8.
Body weight:
All rats gained weight during the observation period.
Gross pathology:
No abnormalities were noted at necropsy

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The test article, BI730357 Nitril was classified as Category 4 in respect of its acute oral toxicity according to
the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) in respect
of its acute oral toxicity.