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Diss Factsheets

Administrative data

Description of key information

Study conducted to recognised testing guidelines with GLP certification.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04 January 1989 to 01 February 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
other: 266108-D
Version / remarks:
16 December 1988
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Limit test:
yes
Specific details on test material used for the study:
Appearance: Red vitreous, high viscosity solid
Storage: Room temperature, away from light
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

Body weight range at initiation of treatment
males: 177.5 to 216.1 g.
females : 146.0 to 174.1 g.

Supplier : IFFA CREDO, Les Oncins, 69210 L‘ARBRESLE, Franc
Number of animals in the study : 40 (20 males and 20 females).
Age at initiation of treatment : 6 weeks.

ENVIRONMENT

Caging : animals housed by five animals of the same sex/group in stainless steel mesh cages (555 x 350 x 200 mm) in an air conditioned building

temperature : 19 to 25°C
relative humidity : 35 to 75 %
air changes : minimum 8 air changes per/hour.
lighting cycle : 12 hours light (artificial) 12 hours dark.

Justification : rodent species acceptable to the regulatory authorities. Background data of the strain available at the testing facility. No known contra-indication to its use.

Diet : Rat & mouse pelleted complete diet ad libitum (Diet reference A04 Usine d'Alimentation Rationnelle, Villemoisson, 91360 Epinay S/Orge, France), sterilised by irradiation and analysed for the absence of chemical and bacteriological contaminants.
Delivered ad libitum.
The animals were fasted for approximately 16 hours before necropsy.

Water filtered (0.6 µm) mains water, ad libitum (automatic watering), analysed twice a year (Laboratoire Municipal d'Hygiène de la Ville de Lyon, France) for chemicals and bacterial contamination.
AnimaI health procedure clinical inspection for ill-health on arrival.

Acclimatisation period: 7 days minimum between reception of the animals and start of treatment.

Allocation to treatment group: done during the acclimatisation period, according to the standard operating procedures of the testing facility : using computer generated random number tables.
Mean body weights of each group will not be statistically significantly different from each other (analysis of variance) each sex being considered separately.



Route of administration:
oral: gavage
Details on route of administration:
Justification of the route : intended route for administration to humans.
Vehicle:
corn oil
Details on oral exposure:
Preparation suspension of the test article in the vehicle at the concentrations of 1, 4 and 10 mg/ml using the following method

The test article (a solid) was fl'agmented and weighed into a labelled beaker. A small quantity of warm (40°C) vehicle was added and the beaker was gently heated on a hot plate to completely melt the test article. The formulation was then stirred and transfered into a calibrated bottle and made up to the appropriate volume with vehicle, some of which was al so used to rinse the preparation beaker . A magnetic stirrer was used to ensure homogeneity.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No details
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 1; Control
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
Group 2; Low
Dose / conc.:
40 mg/kg bw/day (nominal)
Remarks:
Group 3; Intermediate
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Group 4; High
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
Identification numbers :

Group number Males Females

1 01 to 05 21 to 25
2 06 to 10 26 to 30
3 11 to 15 31 to 35
4 16 to 20 36 to 40

Identification of the cages : according to the standard operating procedures of the testing facility : group-related colour card with study number, group number, sex and animal number.
Positive control:
No positive control
Observations and examinations performed and frequency:
No other examinations
Sacrifice and pathology:
PATHOLOGY

Necropsy:

Animals were weighed and killed the day after the last administration by carbon dioxyde anaesthesia followed by exsanguination.

All animals were submitted to full necropsy procedures. The necropsy included examination of:
the external surface
ali orifices
the cranial cavity
the carcass
the thoracic, ab dominai and pelvic cavities and viscera.

Organ weight:
The liver and the brain were weighed for all animals.
Organ weights were expressed as absolute values (g) and as an organ to 100 g of body weight ratio and as an organ to 1 g of brain weight ratio.

Organs/tissues preservation and histopathology: The following organs/tissues were sampled for ali animals.

Organ/tissue sampled: Number of sections examined in histopathology.

Adrenals
Heart
Kidneys
Liver (2 samples from different lobes) 2
Lungs
Spleen
All gross lesions.
Other examinations:
No other examinations.
Statistics:
Presentation of results and statistical analyses
For food consumption, the tables show arithmetical mean and standard deviation. Owing to the method of calculation, no statistical analyses was performed (n = 1).
For body weight, the table shows the number of data (adjusted survival), arithmetical mean and standard deviation (S. D.). An analysis of variance and a Dunnett's t-test were performed to compare the mean values; the table only shows probability value, P, when P < 0.05 .
For organ weights, the tables of mean values give for each different organ weighed :
the number of data (IN GRP)
the arithmetical mean (MEAN)
the standard deviation (STAND DEV)
the difference between the mean of the treated group and that of the control group (GROUP DIF).
For the treated groups, these results are followed by the results of Dunnett's t-test and the analysis of variance.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Body weight gain was slightly reduced in group 4 males but statistical significance was not attained and the individuaI data did not suggest a treatment-related effect.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In comparison with group 1 an increase in the liver weight was observed for the males and the females in groups 3 and 4 with a dose effect relationship for the organ to body weight ratio . This increase achieved statistical significance for the group 4 females only. The opposite nature of the changes observed for the group 2 animals did not indicate an effect of treatment at this dose leve!.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Critical effects observed:
no
Conclusions:
The dose level of 10 mg/kg/ day was a clear no observable effect level.

The dose levels of 40 and 100 mg/kg/day induced a dose-related increase in the liver weight with statistical significance limited to females treated at 100 mg/kg, with no subsequent microscopic changes and in particular no morphological alterations of toxicological relevance.

Executive summary:

The test article (Article A) formulated in corn oil was administered to rats during a 4 week oral toxicity study.

An analytical method supplied by HAZLETON U. K was validated and used to analyse the formulations.

Formulations prepared for week 1 and week 4 were assayed for achieved concentrations.

Test article concentration were within acceptable limits for dosing formulations (deviation from nominal values was 10 % maximum).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
1
Organ:
liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The substance does not meet the criteria for classification in accordance with the classification, labelling and packaging regulation (EC 1272/2008).