Radia 7838

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 08 - October 11, 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study has been performed according to OECD guidelines and according to GLP principles

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

Temporary deviations from the maximum level of temperature of the freezer in which the samples for analyses on the AU400 were stored occurred. These temporary deviations were considered not to have adversely affect the clinical biochemistry results.

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

yes

Remarks:

Temporary deviations from the maximum level of temperature of the freezer in which the samples for analyses on the AU400 were stored occurred. These temporary deviations were considered not to have adversely affect the clinical biochemistry results.

Principles of method if other than guideline:

United States Environmental Protection Agency (EPA). Health Effects Test Guidelines, OPPTS 870.3050, Repeated dose 28- day oral toxicity study in rodents. Office of Prevention, Pesticides and Toxic Substances (7101), EPA 712-C-00-366, July 2000.

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

- Name of test material (as cited in study report): Radiagreen RA
- Physical state: Yellow to amber liquid
- Analytical purity: Unknown
- Lot/batch No.: OE70125
- Expiration date of the lot/batch: 25 January 2011
- Stability under test conditions: Stable
- Storage condition of test material: In refrigerator (2-8ºC) in the dark

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Propylene glycol, specific gravity 1.036.

Details on oral exposure:

Method of administration:
Oral gavage, using a plastic feeding tube.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of formulations were analysed to check homogeneity, stability and accuracy of preparation. See Notox report 485768 for validated analytical method.

Duration of treatment / exposure:

28 days

Frequency of treatment:

7 days/week

No. of animals per sex per dose:

5

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

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

Clinical observations:
No mortality occurred during the study period.
There were no clinical signs of toxicity noted during the observation period.
Functional observations:
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals.
The variation in motor activity did not indicate a relation with treatment.
Body weights:
No toxicologically signficant changes in body weights and body weight gain were noted.
The statis tically significant lower body weight gain of males at 150 and 1000 mg/kg bw/d was of a temporary nature and mean body weight (gain) remained within the range considered normal for rats of this age and strain.
Food consumption:
No toxicologically significant changes in food consumption.
Laboratory findings:
Haematology:
No toxicologically relevant changes occurred in haematological parameters of treated rats.
The statistically significant lower partial thromboplastin time (APTT) and lower relative eosinophil counts of males and females at 1000 mg/kg/day respectively, were of a minor nature and within the range considered normal for rats of this age and strain. Control partial thromboplastin time
values of males were considered to be slightly high. Therefore, these minor statistically significant differences were considered not to represent a change of toxicological significance.

Clinical biochemistry:
No toxicologically relevant changes occurred in clinical biochemistry parameters of treated rats.
The statistically significant higher inorganic phosphate level of males at 1000 mg/kg/day occurred in the absence of a clear dose-related response, and the mean was within the range considered normal for rats of this age and strain. No toxicological relevance was therefore ascribed to this
change.

Effects in organs:
Necropsy did not reveal any toxicologically relevant alterations.

Organ weights and organ to body weight ratios of treated animals were considered to be similar to those of control animals.

There were no microscopic findings recorded which could be attributed to treatment with the test substance.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects at highest dose tested (original NCD unit is mg/kg/day)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Comments:
No toxicologically significant changes in body weights and
body weight gain were noted.

No toxicologically significant changes in food consumption
before or after allowance for body weight were noted.

Applicant's summary and conclusion

Conclusions:

A NOAEL for Radiagreen RA of >=1000 mg/kg/day was established.