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Diss Factsheets

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:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study according to GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report date:
1998

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: flakes

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: males approx. 7 weeks, females approx. 8 weeks
- Weight at study initiation: males 194-238 g, females 145-176 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approx. 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-22.0°C
- Humidity (%): 53-65%
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Daily preparation of the solutions for administration with different substance concentrations according to the intended doses. Stability of the test substance in the solutions for administration were examined before start of the study.

VEHICLE
- Justification for use and choice of vehicle: test substance is not water soluble
- Concentration in vehicle: 0-46.4 mg/mL
- Amount of vehicle (if gavage): 6.81 mL
- Lot/batch no. (if required):1539702 (Lamotte, Bremen)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
In weeks one and three, samples were taken and analysed accordingly by HPLC. The measured concentration were 96.1-104.7% of the nominal concentrations (4.64, 14.7 and 46.4 mg/mL ).
Duration of treatment / exposure:
Test duration: 28d
Frequency of treatment:
Dosing regime: once a day, 7 days a week
No. of animals per sex per dose:
5
additionally 5 in the control and highest dose group as recovery group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selections: based on a preliminary dose range finding study
- Post-exposure recovery period in satellite groups: 6 weeks
Positive control:
no

Examinations

Observations and examinations performed and frequency:
- Cage side observations: once/twice daily
- Weighing: day 0 (prior to dosing), weekly thereafter
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

The following tissues were examined: gross lesions and tissue masses, mandibular lymph node, mammary gland, skin, salivary gland, sternebrae, thyroid gland, small intestine, colon, liver, prostate/testes or ovaries/uterus, lungs and bronchi, heart, esophagus, stomach, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, spinal cord (if neurologic signs present) and eyes (if grossly abnormal).

HISTOPATHOLOGY: Yes

Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned and stained with hematoxylin and eosin.
After completion of the pathology examination, the slides, individual animal data records and summary tables were sent to an independent quality assurance laboratory for evaluation.

Statistics:
DUNNETT-Test for normal distribution, otherwise STEEL test;
significance level: p < 0.05

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
disturbances in coordination, hyper- or hypokinesia in mid and more pronounced in the high dose group; effects faded within 2 weeks post exposure; no mortality
Mortality:
mortality observed, treatment-related
Description (incidence):
disturbances in coordination, hyper- or hypokinesia in mid and more pronounced in the high dose group; effects faded within 2 weeks post exposure; no mortality
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
only the high dose group was affected significantly; during recovery period parameter returned to control level
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduction in food consumption: low and mid dose group 10 to 20%, high dose group up to 30%
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Week 1: slight increase of erythrocytes, hemoglobin, hematokrit and number of plateletes in the highest dose group; week 4: these parameters were reduced. Additionally, reticulocytes, eosinophils and neutrophils appeared slightly altered
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
see Details on test results
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
relative and absolute increase of liver and spleen in the highest dose group
Gross pathological findings:
no effects observed
Details on results:
Clinical chemistry:
Week 1: activity of liver enzymes and conc. of albumin and bilirubin were increased (mid and high dose) and gamma-GT and alpha-1 globulins reduced. Findings were more pronounced in the high dose group; week 4: increased bilirubin and albumin and some liver enzymes; Decreases in cholinesterase, triglycerides and relative amount of globulins; most effects in high dose group only. In week 10 no findings of toxicological relevance were recorded.

Effects in organs:
There were no macroscopic changes observed in any organs.

In the high and medium dose groups, Liver weights were significantly increased. In the high dose group, the Spleen weights were increased.

Histopathological examination revealed minmal to moderate centrolobular hepatocellular hypertrophy that was reversed during the recovery period. In the spleen, a dose-related increase in the severity of extramedullary heamatopoiesis (predominantly erythroid) was recorded. This finding was accompanied by a minimally to mildly decreased myeloid to erythroid cell ratio in the bone marrow. All findings were reversible during the recovery period.

Effect levels

Dose descriptor:
NOEL
Effect level:
ca. 31.6 mg/kg bw/day (nominal)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Liver, blood, and the spleen were identified as target organs. All changes were found to be completely reversible in the dose range tested.
Although there was a slight reduction in food consumption at the low dose level, no other parameters, including body weights, were influenced.
The NOAEL was determined to be 31.6 mg/kg bw, the LOEL 100 mg/kg bw.