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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:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from secondary source.

Data source

Reference
Reference Type:
secondary source
Title:
OPINION ON Picramic acid and sodium picramate COLIPA n° B28
Author:
Scientific Committee on Consumer Safety
Year:
2012
Bibliographic source:
Scientific Committee on Consumer Safety, (SCCS) 18 September 2012

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Repeated dose toxicity study for test substance was conducted in male and female rats for 14 days by oral gavage.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Sodium picramate
- Molecular formula (if other than submission substance): C6H4N3NaO5
- Molecular weight (if other than submission substance): 221.10 g/mol
- Substance type: Organic
- Physical state: Solid
- Impurities (identity and concentrations): 62.4%

Test animals

Species:
rat
Strain:
other: HanBrl:WIST (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
No data available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Bi-distilled water
Details on oral exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Water was used.
- Concentration in vehicle: 0, 20, 100 and 250 mg/kg bw/day
- Amount of vehicle (if gavage): 10 ml/kg bw
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
14 day
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 100 and 250 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
Total no of animals-40
0 mg/kg bw/day -5 male and 5 female.
20 mg/kg bw/day 5 male and 5 female.
100 mg/kg bw/day 5 male and 5 female.
250 mg/kg bw/day 5 male and 5 female.
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data available.

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

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

FOOD EFFICIENCY: No data available.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water studies): No data available.

OPHTHALMOSCOPIC EXAMINATION: No data available.

HAEMATOLOGY: No data available.

CLINICAL CHEMISTRY: No data available.

URINALYSIS: No data available.

NEUROBEHAVIOURAL EXAMINATION: No data available.

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes,
Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals were recorded.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In rats treated at the dose of 250 mg/kg bw/day several clinical signs were observed: during the first treatment week, slightly ruffled fur was observed in one female on treatment days 4 and 5 and in an other one on treatment day 3; slight emaciation was observed in four females and two males in the first treatment week and moderate emaciation in a further male on treatment day 6. Decreased spontaneous activity was observed in one female on treatment day 4 and 5 and in one male on treatment day 6. Slightly brown urine was seen in two females and three males on the last day of treatment.
Mortality:
mortality observed, treatment-related
Description (incidence):
Deaths were observed at the high dose(250 mg/kg bw/day) -two males: Days 5 and 7; three females: Days 1, 3 and 7
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean absolute body weights were decreased in males treated at the dose of 250 mg/kg bw/day. In females of this dose 250 mg/kg bw/day showed, a non -statistically significant decrease was observed.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The mean absolute food intake was slightly decreased in males and females treated at the dose of 250 mg/kg bw/day and the mean relative food intake was also decreased in males and females treated at this dose when compared to control rats
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increased dose-related mean spleen weights and spleen to body ratios were observed in males and females rats treated at 250 mg/kg bw/day. The mean liver to body weight ratio was increased in males treated at the dose of 100 mg/kg bw/day or 250 mg/kg bw/day and in females at the dose of 250 mg/kg bw/day and 100 mg/kg bw/day but at this dose the increase was not statistically significant. An increase of the mean brain to body weight ratio was also observed in male rats at the dose of 250 mg/kg bw/day.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The macroscopic lesions observed and possibly related to treatment consisted of enlarged spleen observed in 3 male rats and 1 female rat of the 250 mg/kg bw group. They could be correlated to the increase of the weight of the spleen.Reduced size of testes, epididymis, prostate and seminal vesicles was seen in three males treated at the dose of 250 mg/kg bw/day.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Changes in colon as foci, nodules or thickened organ were observed in three male rats and one female rats treated at the dose of 250 mg/kg bw/day and in one female rat treated at the dose of 100 mg/kg bw/day.
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Other signs observed were discoloration of lung, lung not collapsed and thickened thymus, but they were not considered to be related to the treatment with test chemical

Effect levels

Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect was observed in clinical change, mortality, body weight, Food intake, organ weight, grosspathology and histopathology.
Remarks on result:
other: No toxic effect were observed .

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 20 mg/kg/day for test substance in Wistar rats by oral (gavage) administration in a 14 day study.
Executive summary:

In a repeated dose toxicity study the effect of test substance was observed in male and female Wistar rats for 14 days. The male and female Wistarrats were exposed to test substance on a daily basis at dose concentration of 0, 20, 100 and 250 mg/kg bw/day.Deaths were observed at the high dose [two males: Days 5 and 7; three females: Days 1, 3and 7].Control animals, animals treated at the dose of 20 mg/kg bw/day or 100 mg/kg bw/day showed no treatment related clinical effects. In rats treated at the dose of 250 mg/kg bw/day several clinical signs were observed:during the first treatment week, slightly ruffled fur was observed in one female on treatment days 4 and 5 and in another one on treatment day 3; slight emaciation was observed in four females and two males in the first treatment week and moderate emaciation in a further male on treatment day 6. Decreased spontaneous activity was observed in one female on treatment day 4 and 5 and in one male on treatment day 6. Slightly brown urine was seen in two females and three males on the last day of treatment. The mean absolute food intake was slightly decreased in males and females treated at the dose of 250 mg/kg bw/day and the mean relative food intake was also decreased in males and females treated at this dose when compared to control rats. The mean absolute body weights were decreased in males treated at the dose of 250 mg/kg bw/day when compared to the control group. In females of this dose group a not statistically significant decrease was observed. The mean body weight gain was decreased in males and females from the high dose group.Increased dose-related mean spleen weights and spleen to body ratios were observed in males and females rats treated at 250 mg/kg bw/day. The mean liver to body weight ratio was increased in males treated at the dose of 100 mg/kg bw/day or 250 mg/kg bw/day andin females at the dose of 250 mg/kg bw/day and 100 mg/kg bw/day but at this dose the increase was not statistically significant. An increase of the mean brain to body weight ratio was also observed in male rats at the dose of 250 mg/kg bw/day. The macroscopic lesions observed and possibly related to treatment consisted of enlarged spleen observed in 3 male rats and 1 female rat of the 250 mg/kg bw group. They could be correlated to the increase of the weight of the spleen and were considered related to the treatment. Reduced size of testes, epididymes, prostate and seminal vesicles was seen in three males treated at the dose of 250 mg/kg bw/day. Changes in colon as foci, nodules or thickened organ were observed in three male rats and one female rats treated at the dose of 250 mg/kg bw/day and in one female rat treated at the dose of 100 mg/kg bw/day. Thickened caecum was observed in three male rats and foci were seen on the caecum of two males and two females treated at the dose of 250 mg/kg bw/day. Other signs observed were discoloration of lung, lung not collapsed and thickened thymus, but they were not considered to be related to the treatment with test substance. Therefore NOAEL was considered to be 20 mg/kg/day for test chemical inWistarrats by oral (gavage) for 14 days.