Registration Dossier

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was conducted between 16 December 2015 and 22 January 2015.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
None
Specific details on test material used for the study:
None

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
Female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non-pregnant. After an acclimatization period of at least five days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were eight to twelve weeks of age. The body weight variation did not exceed ±20% of the body weight of the initially dosed animal.

The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Justification
Rats are the preferred species of choice as historically used for safety evaluation studies and are specified in the appropriate test guidelines.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Test Item Formulation and Experimental Preparation
For the purpose of the study the test item was freshly prepared, as required, as a solution in distilled water.

The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Using available information on the toxicity of the test item, 2000 mg/kg body weight was chosen as the starting dose.

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose level to confirm the survival of the previously dosed animals.

Clinical observations were made 30 minutes, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily.

Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.

At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Statistics:
No data

Results and discussion

Preliminary study:
Dose level: 2000 mg/kg body weight;
Animal Number: 1;
Result: No toxicity was observed.
Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the observation period. Black stained feces was noted in all animals during the study.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
No data

Any other information on results incl. tables

Individual Clinical Observations and Mortality Data

Dose Level mg/kg bw

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Female

0

0

0

0

0F

0F

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0F

0F

0F

0F

0F

0

0

0

0

0

0

0

0

0

0

2-1

Female

0

0

0

0F

0F

0F

0F

0F

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

0

0F

0F

0F

0F

0F

0

0

0

0

0

0

0

0

0

0

2-3

Female

0

0

0

0F

0F

0F

0F

0F

0

0

0

0

0

0

0

0

0

0

0=   No signs of systemic toxicity

F =   Black stained feces

Individual Body Weights and Body Weight Changes

Dose Level

mg/kg

Animal Number
and Sex

Body Weight (g) at Day

Body Weight Gain (g) During Week

0

7

14

1

2

2000

1-0 Female

175

193

205

18

12

2-0 Female

160

175

188

15

13

2-1 Female

166

183

193

17

10

2-2 Female

173

191

194

18

3

2-3 Female

167

187

211

20

24

 

Individual Necropsy Findings

Dose Level
mg/kg bw

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

1-0 Female

Killed Day 14

No abnormalities detected

2-0 Female

Killed Day 14

No abnormalities detected

2-1 Female

Killed Day 14

No abnormalities detected

2-2 Female

Killed Day 14

No abnormalities detected

2-3 Female

Killed Day 14

No abnormalities detected

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar rat was estimated to be >2000 mg/kg body weight.
Executive summary:

The acute oral toxicity of FAT 40868 in Wistar rats was evaluated in a study conducted according to OECD Guideline 420 and EU Method B.1. Following a sighting test at a dose level of 2000 mg/kg bw, additional four fasted female animals were given a single oral dose of test item, as a solution in distilled water, at a dose level of 2000 mg/kg bw. Clinical signs and body weight development were monitored during the following 14 days of observation. All animals were subjected to gross necropsy at the end of the observation period (day 14). No mortality occurred throughout the duration of the study. There were no signs of systemic toxicity. Black stained feces were noted in all animals during the study. All animals showed expected gains in body weight. No abnormalities were noted at necropsy. Hence, based on the findings of the study, the acute oral median lethal dose (LD50) of the test item in the female Wistar rats was estimated to be >2000 mg/kg body weight.