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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From November 7 to December 20, 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
1992
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Red RA 10463
IUPAC Name:
Red RA 10463

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:(WI) BR
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days of treatment
Frequency of treatment:
daily (7 days per week)
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Remarks:
28-day treatment period only
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Remarks:
28-day treatment period only
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
28-day treatment period only
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
28-day treatment period plus additional 14-day recovery period
No. of animals per sex per dose:
5 males and 5 females per group (6 groups in total)
Control animals:
yes, concurrent vehicle
Positive control:
none

Examinations

Observations and examinations performed and frequency:
Mortality/viability (twice daily), clinical signs (at least daily), body weight (weekly), food consumption (weekly), water consumption (subjective appraisal only), ophthalmoscopic examinations (during week 4 (all) and week 6 (recovery groups only)), haematology, biochemistry.
Sacrifice and pathology:
All animals surviving to the end of the observation period were deeply anaesthetised using ether vapour and subsequently exsanguinated. All animals assigned to the study were necropsied and descriptions of all macroscopic abnonmalities recorded. Samples of tissues and organs were collected from all animals at necropsy and fixed in neutral phosphate buffered 4 % formaldehyde solution. All organ and tissue samples were processed, embedded and cut at a thickness of 2 to 4 µm and stained with haematoxylin and eosin.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No clinical signs related to toxicity were observed, however, brown/purple discolouration of the fur, tail and urine occurred. Infrequent alopecia, salivation, rales, scabs and eye injury did not demonstrate relationship to treatment.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The following slight haematological findings were within range of historical values and no correlation to treatment, and for this reason are considered to have arisen by chance and do not represent biological significance: red blood cell count, haemaglobin concentration and haematocrit were slightly decreased, and red cell distribution width was slightly elevated among high-dose females.
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Final liver:body weight ratios were slightly elevated among high-dose males and females, however this finding was statistically significant only among males, and this finding was not evident among the animals which completed a two-week recovery phase. Absolute liver weights were also slightly elevated in this group of males, however this finding was not statistically significant.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Purple staining of the skin/tail among animals treated with 1000 mg/kg bw/day after 4 weeks. Black lungs which adhered to the heart and thymus, plus watery fluid in the thoracic cavity, was observed in one high-dose male only.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Pericarditis in the.heart and pleuritis and haemorrhage in the lungs of one high-dose male was consistent with gavage injury.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 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

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
As no indication was found of morphologic or functional alterations in the liver, NOAEL (sub-acute, oral, rat) = 1000 mg/kg bw/day