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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
Study period:
From January 20, 1999 to February 17, 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
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: particulate/powder
Remarks:
red powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
- Based on guidelines
Sex:
male/female
Details on test animals and environmental conditions:
Origin: Harlan Winkelmann
Acclimatization: at least 5 d
Body weight at start for males: 280 g and for females: 209 g
Age: 5-6 weeks
Temperature and relative humidity: 22 +/-3°C and 50+/-20%, respectively
Lighting time: 12 h daily
Food: ssniff R/M-H (V 1534), ad libitum (except for the period in which the animals were kept in diuresis cages)
Water: tap water, ad libitum (except for the period in which the animals were kept in diuresis cages)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
deionized
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Determination of the solubility, stability and homogenecity of the test substance (3 samples)
- Method: HPLC-separation on a reverse phase column followed by a spectrophotometric detection (515 nm)
- Results obtained: acceptable
Duration of treatment / exposure:
Main test group: 28 d
Recovery group: 14 d
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
62.5 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
On Day 29, five animals from each group were sacrificed and necropsied. The remaining animals from the control and high dose groups were sacrifiecd and necropsied after a recovery period of 14 d.
Volume administered: 5 mL/kg bw/day
Positive control:
-

Examinations

Observations and examinations performed and frequency:
- Behavior and state of health were observed daily
- Body weights and food consumption were recorded twice weekly, and water consumption once weekly
- Once before the first treatment and thereafter once a week detailed clinical observations were performed in all animals outside the home cage in a standard arena (open field). Additionally, the animals were examined for opacity of the refracting media of the eyes, damage to the oral mucosa, and impairment of dental growth
- Neurotoxicological measurements including assessment of sensory function, motor activity, forelimb and hindlimb grip strength were conducted at the end of the treatment period
- Hematological examinations and clinical chemistry were carried at the end of the treatment period and after the recovery period
- Urine analysis was performed at the end of the treatment period and after the recovery period
Sacrifice and pathology:
- During necropsy, the animals were examined for macroscopically visible abnormalities, the main organs were weighed and the organ to body weight ratios calculated. Main organs and tissues were processed for histopathological examination and checked for microscopically visible changes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
- No systemic 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
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
- Slightly decreased albumin values in both sexes from the high dose group and slightly decreased protein concentrations in females from the high dose group
- The serum was discolored salmon pink
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
- The urine showed a salmon pink discoloration in all animals from the high group and a very slight salmon pink discoloration in one male from the intermediate dose group
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
- Kidneys were discolored red in both sexes from the intermediate and high dose group at necropsy. Additionally, light red discoloration of testes and adipose tissue was observed in the animals from the high group
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
- Mixed cellular infiltrations in the submucosa of the stomach in the animals from the intermediate and high dose group were observed, with the severity being dose-dependent
Histopathological findings: neoplastic:
not examined

Effect levels

open allclose all
Key result
Dose descriptor:
NOEL
Remarks:
local effects
Effect level:
62.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Key result
Dose descriptor:
NOEL
Remarks:
systemic effects
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
250 mg/kg bw/day (actual dose received)
System:
gastrointestinal tract
Organ:
stomach
Treatment related:
yes
Dose response relationship:
yes

Applicant's summary and conclusion

Conclusions:
Under the study conditions, the NOELs of the substance for local and systemic effects in rats were determined to be 62.5 mg/kg bw/day and 250.0 mg/kg bw/day, respectively.
Executive summary:

A study was conducted to determine the oral repeated dose toxicity of the substance according to OECD Guideline 407 and EU Method B.7, in compliance with GLP. Five Sprague-Dawley rats per sex per group were administered by oral gavage repeated dose of the substance at 0, 62.5, 250 and 1000 mg/kg bw for 28 d followed by a 14 d recovery period. The solubility, stability and homogeneity of the test formulation were analysed by HPLC and spectrophotometric methods and the results were considered acceptable. Clinical signs and mortality were observed daily. Body weights and food consumption were recorded twice weekly, and water consumption was recorded once weekly. Once before the first treatment and thereafter once a week, detailed clinical observations were performed in all animals in an open field. Additionally, the animals were examined for opacity of the eyes, damage to the oral mucosa, and impairment of dental growth. Neurotoxicological measurements including assessment of sensory function, motor activity, forelimb and hindlimb grip strength were conducted at the end of the treatment period. Hematological and clinical chemistry measurements were carried out at the end of the treatment period and after the recovery period. Urine analysis was performed at the end of the treatment period and after the recovery period. During necropsy, the animals were examined for macroscopically visible abnormalities and organ weights. Selected organs and tissues were processed for histopathological examination. No evidence of systemic toxicity was observed except for slightly decreased albumin levels in both sexes and slightly decreased protein concentrations in females from the high dose group. Microscopically, mixed cellular infiltrations in the submucosa of the stomach at the mid and high dose groups were observed, suggestive of localised irritation in the stomach. Under the study conditions, the NOELs of the substance for local and systemic effects in rats were determined to be 62.5 mg/kg bw/day and 250.0 mg/kg bw/day, respectively (Hofmann, 1999).