Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non guideline dose range finding study, not conducted in accordance with GLP. Raw data available.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Test guideline
Qualifier:
no guideline followed
Guideline:
other: 14d-Dose Range Finding Study
Principles of method if other than guideline:
The main objective of the study is to assess whether rats tolerate the test substance at offered concentration by gavage in order to select dose levels in an adequate form of administration for subsequent studies.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance No.: 10/0408-2
Batch identification: 45296088Q0
Purity: Sum of isomers: 99.1 area-% (water content accounted for)
Homogeneity: given (visually)
Stability: given until 28 Feb 2014
The stability of the test substance under storage conditions over the test period was guaranteed by the sonsor and the sponsor holds this responsibility.
Date of production: 16 Jan 2011
Physical state/appearance: liquid/colorless to yellowish
Storage conditions: room temperature, avoid temperatures >50°C

Test animals

Species:
rat
Strain:
other: Crl:WI(Han)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
two weeks
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, and 150 mg/kg bw
Basis:
nominal in water
No. of animals per sex per dose:
four
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
Mortality
A check for moribund and dead animals will be made twice daily from Monday to Friday and once daily on Saturday, Sunday and public holidays.

Clinical signs
Animals will be checked daily for any abnormal clinical signs before the administration, as well as, within 2 hours and within 5 hours after the administ

Food consumption
Food consumption will be determined on study day 3, 7, 10 and 14 and calculated as mean food consumption in gram per animal and day.

Drinking water consumption
Drinking water consumption will be determined on study day 3, 7, 10 and 14 and calculated as mean water consumption in gram per animal and day.

Body weight
Body weight will be determined before the start of the administration period in order to randomize the animals. During the administration period the body weight will be determined on day 0, 3, 7, 10 and 14. The difference between the body weight on the respective day of weighing and the body
weight on day O will be calculated as body weight change.

CLINICAL PATHOLOGY
Blood samples will be taken from fasted animals by puncturing the retrobulbar venous plexus under isoflurane anesthesia. Blood sampling and examination will be carried out in a randomized sequence.
Sacrifice and pathology:
Necropsy
All animals will be sacrificed by decapitation under isoflurane anesthesia. The exsanguinated animals will be necropsied and assessed by gross pathology, special attention being given to the reproductive organs. Animals which die intercurrently or are sacrificed in a moribund state will be necropsied as soon as possible after their death and assessed by gross pathology

Organ weights
The following weights will be determined in all animals sacrificed on schedule:
1. Anesthetized animals
2. Adrenal glands
3. Heart
4. Kidneys
5. Liver
6. Spleen

Organ/Tissue fixation
The following organs or tissues will be fixed in 4% buffered formaldehyde solution:
1. All gross lesions
2. Adrenal glands
3. Heart
4. Kidneys
5. Liver
6. Spleen

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related

Effect levels

Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day (nominal)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

50 mg/kg bw

findings:

salivation in 3/4 males and females

piloerection in 4/4 males and females

food consumption

decreased over entire study period in all males and in females from study days 3 to 14

water consumption

NAD

body weight

decreased in males on study days 7, 10 and 14 as well as in females on study days 7 and 14

body weight change

decreased in males and females over the entire study period

organ weights

absolute terminal body weights: decrease in males and females

adrenal glands and heart: relative weight increased in males

kidneys: relative weight increase in males and females

liver: relative weight increase in males and females

gross lesions

NAD

microscopic lesions

necrosis/fibrosis of the myocard of the heart in 2/4 male and 214 female animals mostly in the septal area

150 mg/kg bw

findings

premature death in 1/4 males on study day 6

poor general condition in 3/4 males and 4/4 females

salivation 2/4 males and 3/4 females

limbs paresis 1/4 males and 2/4 females

ataxia in 1/4 males and 2/4 females

unsteady gait in 1/4 males

all animals were sacrificed in moribund state on study day 6

food consumption

decreased in males and females from study days 0 to 3

water consumption

NAD

body weight

decreased in males on study day 3

body weight change

decreased in males from study day 0 to 3

gross lesions

forestomach erosion/ulcer in 4/4 males and females

grandular stomach erosion/ulcer in 1 /4 males

enlarged liver 4/4 males and females

discoloration of spleen 4/4 males and females

microscopic lesions

necrosis/fibrosis of the myocard of the heart in all male and female animals mostly in the septal area

Applicant's summary and conclusion