Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted to OECD guidelines and to GLP. However as this study is used in the context of a read across, Klimisch 2 is assigned.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Housing: individually in suspended stainless stell wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70%
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
maize oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
50 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
150 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
500 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Dosage levels were selected by the sponsor based on available data from previous studies.
- Rationale for animal assignment (if not random): Random
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): Random

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Days 25 and 38
- Dose groups that were examined: All


HAEMATOLOGY: Yes
- Time schedule for collection of blood: On sacrifice
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: All



CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At necrospy
- Animals fasted: Yes
- How many animals: All


URINALYSIS: Yes
- Time schedule for collection of urine: Overnight prior to sacrifice
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Abbreviated battery on weeks 1 and 2. Full battery on weeks 3 and 5
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength / motor activity

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Parametric and count data were analyzed by One-Way analysis of Variance (ANOVA). If significance was detected, pair-wise group comparisons proceeded using the Tukey-Kramer test. Ranked data were analysed by Kruskall Wallis non-parametric ANOVA, followed by Dunn's test. Descriptive and quantatative data were analyzed by fisher's Exact test. Group by group comparison was undertaken using the Chi-Square test.

Absolute and relative organ weights and clinical pathology data were analyzed for homogeneity of variance using Levene's test, then Kruskal-Wallis non-parametric ANOVA, followed by Dunn's test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
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:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality or significant clinical abnormalities were observed during the main or recovery phases of this study.

BODY WEIGHT AND WEIGHT GAIN
In the males, a statistically significant decreased bodyweight gain was observed in the top dose group. A decrease in bodyweight gain (not statistically significant) was observed in the next highest dose group. However, these decreases were less than 10%, and therefore of questionable statistical significance.

In females, no statistically significant changes were observed.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Statistically significant decreases in food consumption occurred in the second highest group males and the top dose group females.

FOOD EFFICIENCY
Not recorded.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Not recorded.

OPHTHALMOSCOPIC EXAMINATION
No treatment related effects occurred.

HAEMATOLOGY
No biologically significant changes occurred.

CLINICAL CHEMISTRY
No biologically significant changes occurred.

URINALYSIS
No biologically significant changes occurred.

NEUROBEHAVIOUR
No biologically significant changes occurred.

ORGAN WEIGHTS
No biologically significant changes occurred.

GROSS PATHOLOGY
No adverse gross pathology occurred in treated animals.

HISTOPATHOLOGY: NON-NEOPLASTIC
Irritation of the non-glandular stomach occurred in the two highest dose group males and the three highest dose group females.This irritation appeared to be transient. Minimal oedema in the submucosa was observed in the second highest dose group males and minimal to mild oedema in the submucosa and minimal epithelial hyperplasia was observed in the highest dose group males. However, these effects were not observed after the reovery phase.

Minimal oedema in the submucosa, minimal haemorrhage, minimal epithelial hyperplasia, mild inflammation and a mild ulcer occurred in females in the second highest dose group. Minimal oedema in the submucosa and minimal to mild epithelial hyperplasia was observed in females in the top dose group.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not recorded.

HISTORICAL CONTROL DATA (if applicable)
Not recorded.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Average body weights and body weight gains during 28 days of treatment

 

Dose rate (ppm)

Body Weights (g)

 

Total Weight Gain

Week 0

Week 1

Week 2

Week 3

Week 4

g               

% of control

Male

 0

 268

302

331

358 

372 

104

 139

50

 268

303 

335 

359 

373 

105

 139

150

 267

301 

330 

360 

370 

103

 139

500

 263

290 

312 

327 

340 

77

 129

1000

267

298

324

340

351

83

131

Female

  0

 186

203 

216 

228 

263 

50

 141

50

 186

206 

222 

235 

239 

53

 128

150

 184

199 

214 

223 

235 

50

 128

500

 187

202 

212 

224 

228 

41

 122

1000

184

202

211

226

229

45

125

 

Applicant's summary and conclusion

Conclusions:
A NOAEL of 1000 mg/kg bw/day was identified in this study.
Executive summary:

In a subacute toxicity study  was administered to 5 Sprague-Dawley rats/sex/dose via gavage at dose levels of 0, 50, 150, 500, or 1000 mg/kg bw/day).

 

No dose related effects occurred. The NOAEL is 1000 mg/kg bw/day.

 

This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in rats.