Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From May 13th to September 16th, 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
Adopted July 27th, 1995
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Adopted September 30th, 1996
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Yellow 6314-PPT
IUPAC Name:
Yellow 6314-PPT
Test material form:
solid

Test animals

Species:
rat
Strain:
Wistar
Remarks:
HanBrl
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: carboxymethylcellulose 0.5%(w/v) - polysorbate (TWEEN) 80 0.1% (w/v) in distilled water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Test duration: 28 days
14-day recovery for 5 animals per sex in control group and 1000 mg/kg bw/day group
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Male:10 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 10 animals at 1000 mg/kg bw/day

Female:10 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 10 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
General clinical signs, detailed clinical observations, food consumption and body weights were recorded periodically during pretest, the treatment and recovery periods. Functional observational battery and locomotor activity tests were peformed during week 4. At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for hematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals and all gross lesions from all animals. ln addition, kidney, liver, ovaries, uterus, and vagina were examined in animals of groups 2 and 3 and of the recovery group.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Single incidences of eye lesions (eye, opaque) in high dose males and in low dose females were not dose-related and not associated with the treatment. The detailed observations revealed isolated findings of inactivity, fecal boli and opaque eye. None of these findings were considered of toxicological relevance.
Mortality:
no mortality observed
Description (incidence):
All animals survived to the scheduled necropsies.
Body weight and weight changes:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no toxicologically relevant changes to hematology parameters. A number of significant changes were recorded for mid and high dose males and females. All of them were considered of no toxicological relevance since they were either covered by the historical control range, did not display a dose-relationship, or represented isolated findings at the end of the treatment or recovery period without physiological or histopathological correlations.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
The significantly lower glucose plasma concentrations in low and high dose females (50 and 1000 mg/kg) showed no dose-relationship and were fully reversible within the 2-week recovery period. This effect was, therefore, considered of a non-adverse nature. A number of significant changes were recorded for male and female groups. All of them were considered of no toxicological relevance since they were either covered by the historical control range, did not display a dose-relationship, or represented isolated findings at the end of the treatment or recovery period without physiological or histopathological correlations.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no toxicologically relevant changes to urine analysis parameters. A number of significant changes were recorded for high dose males. All of them were considered of no toxicological relevance since they were covered by the historical control range.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were no relevant changes to the parameters investigated (grip strength, landing foot splay, temperature).
There were no relevant changes to the parameters investigated (distance, number of rearings, center time).
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
The absolute and relative mean organ weights at the end of both treatment and recovery period were not affected at a relevant extent. The significantly higher mean kidney weight in low dose males revealed no dose-relationship and was covered by the historical control range. The significantly higher relative thymus weight in high dose males was within the historical control range. ln the absence of histological changes these findings were considered of no toxicological relevance.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Few macroscopic findings were observed in this study. They occurred in comparable numbers in all experimental groups and were similar to those occurring spontaneously in laboratory rats of this strain and age. Thus, no experimental relevance is attributed to these findings.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Liver: glycogen deposition was increased in females at 1000 mg/kg. ln the other male and female control and treated groups the incidence and average grading of this finding were comparable, but the higher grades of severity occurred only in treated animals when compared to controls. After the recovery period, the incidence and grading of this finding were similar in control and treated groups.

A variety of other changes was found in this study. They commonly occur in laboratory rats of this strain and age, and, neither their incidences nor their distribution or morphologic appearance gave any indication of a treatment-related association.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, 1000 mg/kg bw/day of test item was established as NOAEL.