Sodium 2-amino-4,6-dinitrophenoxide

Endpoint summary

Description of key information

Repeated dose toxicity: via oral route;

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

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance sodium 2-amino-4,6-dinitrophenolate ( 831-52-7) which is reported as 3.36E¹³mmHg at 25 C. Thus, exposure to inhalable dust, mist and vapour of the chemical sodium 2-amino-4,6-dinitrophenolate is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for sodium 2-amino-4,6-dinitrophenolate ( 831-52-7) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that sodium 2-amino-4,6-dinitrophenolate shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that sodium 2-amino-4,6-dinitrophenolate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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.

Qualifier:

according to guideline

Guideline:

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

Species:

rat

Strain:

other: HanBrl:WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

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

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

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.

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

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 .

Critical effects observed:

not specified

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is published by european commission.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The data available for the test chemical was reviewed to determine the toxic nature of sodium 2-amino-4,6-dinitrophenolate ( 831-52-7)repeated exposure by oral route. The study is as mentioned below:

Repeated dose toxicity: via oral route;

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 in Wister rats by oral (gavage) for 14 days.

In a repeated dose toxicity study the effect of test substance was observed in male and female Wistarrats for13 weeks. The male and female Wistarrats were exposed to test substance on a daily basis at dose concentration of 0, 5, 15 and 80 mg/kg bw/day. No mortality was observed during the study.At high dpse group 80 mg/kg bw/d: increase in food consumption in male and female rats; haematological changes in male and female rats; clinical biochemistry changes (metabolic changes); increase in liver (reversible increase), kidney and spleen weight and decrease in testes weights (irreversible increase) and tubular degeneration; ulceration or inflammation of the caecum in both male and female rats hemopoiesis extra or intra medullary, vacuolation in the adrenals of male rats were observed. At 15 mg/kg bw/d: haematological changes was observed in female rats; ulceration or inflammation of the caecum in female rats, microscopic findings in the kidney and liver in female and male rats were observed.

Therefore No Observed Adverse Effect Level (NOAEL) in rats after daily oral treatment is determined to be 5 mg/kg bw/day, corresponding to 3.1 mg/kg bw/day active ingredient.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance sodium 2-amino-4,6-dinitrophenolate ( 831-52-7) which is reported as 3.36E¹³mmHg at 25 C. Thus, exposure to inhalable dust, mist and vapour of the chemical sodium 2-amino-4,6-dinitrophenolate is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for sodium 2-amino-4,6-dinitrophenolate ( 831-52-7) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that sodium 2-amino-4,6-dinitrophenolate shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that sodium 2-amino-4,6-dinitrophenolate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

 

Based on the data available for the test chemical sodium 2-amino-4,6-dinitrophenolate ( 831-52-7) not likely to exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the test chemical sodium 2-amino-4,6-dinitrophenolate ( 831-52-7) not likely to exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.