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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
23 Sep 2003 - 07 Apr 2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-guideline study with acceptable restrictions (lack of details on test substance, no urine analysis performed).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
lack of details on test substance; no urine analysis performed.
GLP compliance:
yes (incl. QA statement)
Remarks:
the Department of Health of the Government of the United Kingdom
Limit test:
no

Test material

Constituent 1
Reference substance name:
163961-32-8
Cas Number:
163961-32-8
IUPAC Name:
163961-32-8
Details on test material:
- Name of test material (as cited in study report): only trade name given
- Physical state: pale yellow liquid
- Analytical purity: no data
- Storage: room temperature in the dark

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent.
- Age at study initiation: 5-6 weeks
- Weight at study initiation: males weighed 189 to 235 g, and females weighed 142 to 203 g
- Housing: groups of 5 animals in polypropylene grid-floor cages suspended over trays lined with absorbent paper
- Diet: pelleted diet (Rodent 5LF2 (Certified) Diet, lnternational Product Supplied Ltd., Northants, UK), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: 14 days
Environmental enrichment was provided in the form of wooden chew blocks (B & K Universal Ltd., Hull, UK) and cardboard fun tunnels (Datesand Ltd., Cheshire, UK).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Air changes (per hr): 55 ± 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Dose volume: 4 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken once weekly of each test material formulation and analysed for concentration at Safepharm Analytical Laboratory.
The results indicate that the prepared formulations were within ± 10 % of nominal.
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
5, 50 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
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: All animals were examined for overt signs of toxicity, ill-health or behavioural change immediately before dosing and one and five hours after dosing during the working week.
Animals were observed immediately before dosing and one hour after dosing at weekends and on public holidays.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
Food consumption was recorded for each cage group (5 animals) at weekly intervals throughout the study

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: daily, for each cage group by visual inspection of the water bottles for overt changes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: The eyes of all control and high dose animals were examined pre-treatment, and all treatment
groups were examined prior to termination of treatment (during Week 12).

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all surviving animals
- Parameters checked: Hb, RBC, Hct, MCH, MCV, MCHC, total leucocyte count, differential leucocyte count, platelets, reticulocytes, Prothrombine time, Activated partial thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination
- Animals fasted: No data
- How many animals: all surviving animals
- Parameters checked: Urea, Glucose, total protein, albumin, sodium, potassium, chloride, calcium, inorganic phosphorus, ASAT, ALAT, AP, Creatinine, total cholesterol, total bilirubin

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: weekly
- Dose groups that were examined: all surviving animals
- Battery of functions tested: sensory activity / grip strength / motor activity:
- - Behavioural Assessment

ORGAN WEIGHTS:
Adrenals, Brain, Epididymides, Heart, Kidneys, Liver, Ovaries, Spleen, Testes, Thymus, Uterus

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
On completion of the dosing period all surviving animals were killed by intravenous overdose of sodium pentobarbitone followed by exsanguination. All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.

HISTOPATHOLOGY: Yes
Samples of the following tissues were removed from all animals and preserved:
Adrenals, Aorta (thoracic), Bone & bone marrow (femur including stifle joint), Bone & bone marrow (sternum), Brain (including cerebrum, cerebellum and pons), Caecum, Colon, Duodenum, Epididymides, Eyes, Gross lesions, Heart, Ileum (including Peyer's patches), Jejunum, Kidneys, Liver, Lungs (with bronchi), Lymph nodes (cervical and mesenteric), Mammary glands, Muscle (skeletal), Oesophagus, Ovaries, Pancreas, Pituitary, Prostate, Rectum, Salivary glands (submaxillary), Sciatic nerve, Seminal vesicles, Skin (hind limb), Spinal cord (cervical, mid-thoracic and lumbar), Spleen, Stomach, Testes, Thymus, Thyroid/parathyroid, Tongue, Trachea, Urinary bladder, Uterus
All tissues were despatched to Propath UK Ltd., Willow Court, Netherwood Road,, Rotherwas, Hereford, UK for processing (Principal Investigator: H Young).

Initially, tissues from all control and high dose groups were prepared as paraffin blocks, sectioned at nominal thickness of 5 μm and stained with haematoxylin and eosin for subsequent microscopic examination. Since there were indications of treatment-related hepatic changes, examination was subsequently extended to include similarly prepared sections of liver tissue from all animals in the other treatment groups.
Microscopic examination was conducted by the Study Pathologist. All findings were entered into the ROELEE Pathology computerisation system for tabulation and report production.
Statistics:
Haematological, blood chemical, organ weight (absolute and relative to terminal bodyweight), weekly bodyweight gain and quantitative functional performance and sensory reactivity data were assessed for dose response relationships by linear regression analysis, followed by one way analysis of variance (ANOVA) incorporating Levene's test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett's test. Where Levene's test showed unequal variances the data were analysed using non-parametric methods: Kruskat-Wallis ANOVA and Mann-Whitney 'U' test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
considered non-adverse
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
considered non-adverse
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
considered non-adverse
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no deaths during the study. No clinical signs of systemic toxicity were observed.

BODY WEIGHT AND WEIGHT GAIN
No adverse effect on bodyweight gain was detected during the study.

FOOD CONSUMPTION AND FOOD EFFICIENCY
No adverse effect on dietary intake or food efficiency (the ratio of bodyweight gain to dietary intake) was detected for test animals in comparison to controls during the study.

WATER CONSUMPTION AND COMPOUND INTAKE
Daily visual inspections of water bottles revealed no overt intergroup differences.

OPHTHALMOSCOPIC EXAMINATION
No treatment-related ocular effects were detected.

HAEMATOLOGY
No treatment-related effects were detected.

CLINICAL CHEMISTRY
Males treated with 1000 mg/kg/day showed statistically significant increases in cholesterol and creatinine levels (p < 0.05).

NEUROBEHAVIOUR
There were no treatment-related changes in the functional performance parameters measured.
There were no treatment-related changes detected in the sensory reactivity parameters measured.

ORGAN WEIGHTS
Elevated liver weights, both absolute and relative to terminal bodyweight were detected for animals of either sex treated with 1000 mg/kg/day (p < 0.001). Elevated adrenal weight was also observed for females treated with 1000 mg/kg/day (absolute p < 0.01, relative p < 0.05). An increase in absolute spleen weight (p < 0.05) in 1000 mg/kg/day males and an increase in relative kidney weight (p < 0.01) was also observed for 1000 mg/kg/day females, however, in the absence of the supporting histopathological evidence to suggest an effect of treatment, were considered to be unrelated to treatment.

GROSS PATHOLOGY
No treatment-related macroscopic abnormalities were detected.

HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment-related observed changes:
A marginal effect on hepatocyte size was observed in relation to treatment for female animals treated with 1000 mg/kg/day with a few animals from this group demonstrating centrilobular hepatocyte enlargement (p < 0.05). A similar effect was not convincingly seen for 1000 mg/kg/day males, or for animals of either sex treated with 50 or 5 mg/kg/day.
No other treatment-related changes were observed.

Effect levels

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Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: clinical sings, body weight, food consumption, food efficiency, water consumption, ophthalmoscopic examination, hematology, clinical chemistry, neurobehavioural examination, organ weights, gross necropsy and histopathological examinations.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion