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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
22 Dec 2009 - 29 Mar 2010
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study, but with significant deviations. Since this study was a range-finder for a reproductive toxicity study, only 3 animals per sex and dose were used in the test and major endpoints for the evaluation of systemic toxicity such as haematology, histopathology and clinical biochemistry were not addressed. Thus, this study is insufficient for the evaluation of systemic toxicity after repeated exposure.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD 421
Deviations:
yes
Remarks:
only 3 animals per sex per dose level, no haematology, no clinical biochemistry, no histopathology
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 200-260 g (males) and 140-200 g (females)
- Housing: animals were housed in groups of up to three in open macrolon cages type 2000P (TechniPlast).
- Diet: maintenance diet for rats and mice, No. 1324 TPF, ad libitum.
- Water: autoclaved community tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 30-70%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The suspension of the test item in corn oil was prepared daily.

VEHICLE
- Justification for use and choice of vehicle (if other than water): As the test item’s solubility in water is poor, corn oil was used as an organic solvent. Pre tests showed that the solubility of the test item in corn oil was sufficient. Corn oil is well investigated as vehicle for toxicity studies, and it is explicitly recommended in the OECD 421.
- Amount of vehicle: 4 mL
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily, 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
3
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly and once before beginning of application

BODY WEIGHT: Yes
- Time schedule for examinations: once weekly and once before beginning of application. Females during pregnancy: Day 0, 7, 14, 20, within 24 h post parturition and Day 4 post partum.

FOOD CONSUMPTION: Yes
- Time schedule: once weekly

WATER CONSUMPTION: Yes
- Time schedule: twice weekly
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: laboured breathing, increased salivation and bleeding at the mucous membranes
Mortality:
mortality observed, treatment-related
Description (incidence):
1000 mg/kg bw/day: laboured breathing, increased salivation and bleeding at the mucous membranes
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
At Day 1, all animals treated with the high dose of the test item wiped their mouth in the cage bedding material immediately after application for approximatel 30 seconds, indicating discomfort. From Day 1 to approximately Day 6, all animals from the high dose group showed laboured breathing, increased salivatio and in two instances bleedings at the mucous membranes of mouth and nose. No bleedings or laboured breathing were observed after week one of application. Other than these, no clinical / behavioural signs, stereotypies, or behavioural reactions were observed.

BODY WEIGHT AND WEIGHT GAIN
No effects on body weight gain were observed in animals of the low- and high-dose group. The mean body mass and the mean relative body mass gain of male rats treated with the high dose were slightly reduced in week one when compared to the vehicle control group, but a net body mass loss did not occur. As a tendency, that effect was present but reduced during week two of the pre-mating phase. However, since this tendency diminished towards the end of the in-life phase, a clear indication for toxicity of the test item at the high dose could not be substantiated.

FOOD CONSUMPTION
No changes in food consumption of the animals were observed.

WATER CONSUMPTION AND COMPOUND INTAKE
No changes in daily mean relative water consumption of the animals were apparent.

NECROPSY FINDINGS
No irregular findings indicating toxicological effects of the test item were detected at necropsy (no further information).

Effect levels

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion