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Description of key information

Repeated dose toxicity: Oral

The purpose of this study was to evaluate the toxicity of the test chemical in Sprague-Dawley Rats. Sprague-Dawley Rats were given the test chemical in diet at dose of 20000 ppm (1000 mg/Kg). Body weight, food consumption, Haematology, Clinical chemistry, Urinalysis, gross and histopathology were examined in the treated animals. No Statistically significant difference were observed in body weight, Organ weight, food consumption, Haematology, Clinical chemistry, Urinalysis in treated as compared to control. No test material related lesions were observed during gross and microscopic studies. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) of the test chemical on Sprague-Dawley Rats in 13 weeks study was considered to be at a dose concentration of 20000 ppm (1000 mg/kg bw/day).

Repeated dose toxicity: Inhalation

The particle size distribution of the test substance was found to vary in the size of 53-500 µm, so the potential for the generation of inhalable forms is low. Moreover the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore repeated dose toxicity by inhalation route was considered to be waived.

Repeated dose toxicity: Dermal

Since the substance is used in solid form there is very low probability of the substance penerating the skin. Further the results are negative for skin sensatization and skin irritation. Therefore this end point for repeated dose toxicity by dermal route of exposure 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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Subacute toxicity of the test chemical was assessed in Sprague-Dawley Rats in 13 weeks study
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: A.R. Schmidt Co., Madison, Wisconsin
- Age at study initiation: No data
- Weight at study initiation: N/A
- Fasting period before study: N/A
- Housing: N/A
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: N/A

ENVIRONMENTAL CONDITIONS
- Temperature (°C): N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light): N/A

IN-LIFE DATES: From: To: N/A
















Route of administration:
oral: feed
Details on route of administration:
No data
Vehicle:
other: Diet
Details on oral exposure:
DIET PREPARATION: The test chemical was mixed with feed at dose level of 0 or 20000 ppm (0 or 1000 mg/Kg/day)

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Diet
- Concentration in vehicle: 0 or 20000 ppm (0 or 1000 mg/Kg/day)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentration:
0 or 20000 ppm (0 or 1000 mg/kg bw/day)
Basis:

No. of animals per sex per dose:
Groups of 10 rats of each sex
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, the animals were observed for reactions if any

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes / No / No data
- Growth was measured weekly during the experiment

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- food consumption was measured weekly during the experiment

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Hematologic studies (erythrocyte count, total and differential leukocyte count, hemoglobin concentration, and hematocrit determination) were conducted prior to initiation of test feeding, mid-way through the exposure period, and immediately preceding sacrifice.

CLINICAL CHEMISTRY: Yes
- Clinical blood chemistry studies (fasting blood glucose concentration, blood urea nitrogen concentration, serum alkaline phosphatase activity, and serum glutamic - pyruvic transaminase activity) were conducted prior to initiation of test feeding, mid-way through the exposure period, and immediately preceding sacrifice.

URINALYSIS: Yes
- Urinalysis (albumin, glucose, microscopic elements, pH, and specific gravity) were conducted prior to initiation of test feeding, mid-way through the exposure period, and immediately preceding sacrifice.

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, Gross pathologic examination was conducted on all animals during 13 weeks

HISTOPATHOLOGY: Yes, Histopathological evaluation of tissues 5 rats of each sex from the same groups evaluated hematologically was performed. Weights of the liver, kidneys, spleen, gonads, heart, and brain were obtained at sacrifice
Statistics:
Student t test were used for statistical analysis
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No apparent deleterious effects were produced by the feeding of up to 20 000 ppm (1000 mg/Kg) test chemical
Mortality:
mortality observed, treatment-related
Description (incidence):
One male rat fed the highest level of the 3 chemicals in combination, died during the second week of testing. Symptoms of respiratory infection preceded death and histologic examination of lung tissue confirmed this to be the probable cause of death. No other mortalities occurred and no unusual behavioral reactions were observed in any of the rats during the 13-week feeding period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant differences between the growth of test and control rats were observed
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption data, collected weekly during the experiment, did not reveal any significant differences in the eating patterns of test animals
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Clinical blood chemistry values obtained from animals immediately preceding sacrifice did not reveal any treatment-related changes.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Evaluation of urine throughout the study revealed no changes which could be correlated with ingestion of the test compound.
Behaviour (functional findings):
not examined
Description (incidence and severity):
No unusual behavioral reactions were observed in any of the rats during the 13-week feeding period
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Organ weights including those of the liver, kidneys, spleen, gonads, heart, and brain as well as the corresponding organ to body weight ratios were not different from those of the control animals.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Gross evaluation of tissues from rats treated with the test chemical did not reveal any test material-related lesions.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Body weight, food consumption, Haematology, Clinical chemistry, Urinalysis, gross and histopathology for sodiumsacharrin given alone
Critical effects observed:
not specified

Table: Mean body weights of rats fed the test chemical

Concentration (ppm)

Male rats

Female rats

0

338

174

20000

336

168

 

Table: Hematologic data

Concentration (ppm)

Erythrocyte count (103/mm3)

Leukocyte count (103/mm3)

Hemoglobin concentration (g/mL)

Hematocrit (%)

0

6.7/6.2*

18.4/13.5

14.2/13.6

52/50

20000

7.8/6.4

20.3/15.5

14.3/13.6

52/49

Male value/female value

Table: Clinical Blood Chemistry data

Concentration (ppm)

BUN (mg%)

Fasting blood glucose (mg/100mL)

SAP (K-A units)

SGPT (Dade units)

0

18/22*

70/74

12/12

49/17

20000

20/22

70/78

14/12

49/44

Male value/female value

Conclusions:
The No Observed Adverse Effect Level (NOAEL) of the test chemical on Sprague-Dawley Rats in 13 weeks study was considered to be at a dose concentration of 20000 ppm (1000 mg/kg bw/day)
Executive summary:

The purpose of this study was to evaluate the toxicity of the test chemical in Sprague-Dawley Rats. Sprague-Dawley Rats were given the test chemical in diet at dose of 20000 ppm (1000 mg/Kg). Body weight, food consumption, Haematology, Clinical chemistry, Urinalysis, gross and histopathology were examined in the treated animals. No Statistically significant difference were observed in body weight, Organ weight, food consumption, Haematology, Clinical chemistry, Urinalysis in treated as compared to control. No test material related lesions were observed during gross and microscopic studies. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) of the test chemical on Sprague-Dawley Rats in 13 weeks study was considered to be at a dose concentration of 20000 ppm (1000 mg/kg bw/day).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is K2 peer reviewed publication

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Data available for the target chemical was reviewed to determine the mutagenic nature of the test chemical. The studies are as mentioned below:

Repeated dose toxicity: Oral

The purpose of this study was to evaluate the toxicity of the test chemical in Sprague-Dawley Rats. Sprague-Dawley Rats were given the test chemical in diet at dose of 20000 ppm (1000 mg/Kg). Body weight, food consumption, Haematology, Clinical chemistry, Urinalysis, gross and histopathology were examined in the treated animals. No Statistically significant difference were observed in body weight, Organ weight, food consumption, Haematology, Clinical chemistry, Urinalysis in treated as compared to control. No test material related lesions were observed during gross and microscopic studies. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) of the test chemical on Sprague-Dawley Rats in 13 weeks study was considered to be at a dose concentration of 20000 ppm (1000 mg/kg bw/day).

Another study was performed to evaluate the repeated dose oral toxicity of the test chemical in Beagle dogs. Beagle dogs were given the test chemical alone at dose of 20000 ppm alone 20000 ppm (500 mg/Kg/day) for 16 weeks. Body weight, food consumption, Haematology, Clinical chemistry, Urinalysis, gross and histopathology were examined. No Statistically significant difference were observed in body weight, Organ weignt, food consumption, Haematology, Clinical chemistry, Urinalysis in treated as compared to control. No test material related lesions were observed during gross and microscopic studies. Based on the observations made, the no Observed Adverse Effect Level (NOAEL) of the test chemical on Beagle dogs  in 16 weeks study was observed at dose concentration of 20000 ppm (500 mg/kg bw/day).

Yet another study was performed to evaluate the immune competence of rats fed diets containing high concentrations of the test chemical. The test chemical was administered in feed to male CD-COBS rats for the period of 25 to 54 days at dose concentration of 0, 1, 2.5 or 5% (0, 1666.66, 4166.66, 8333.33 mg/kg bw/day) saccharin per day. The test chemical showed marked, dose-dependent suppression of primary humoral antibody production against SRBC. In contrast to this PFC response, PHA blastogenesis was relatively unaffected, borderline suppression being observed only in one experiment at one PHA concentration. Increase in body weight was also observed in treated group as compared to control group. Therefore, Low Observed Adverse Effect Level (LOAEL) of the test chemical in CD-COBS rats for the period of 25 to 54 days was considered at dose concentration of 1666.66 mg/kg bw/day

In another study, combined repeated dose & carcinogenicity was performed to determine the toxic nature of the test chemical upon repeated exposure by oral route. Spargue dawley rats were fed the test chemical in the diet at dose level of 0 or 5% (0 or 2500 mg/Kg/day) for 80 weeks. During the study period, the test animals were observed for general condition, mortality, body weight changes, food consumption and the animals were subjected to gross and histopathology. The general condition of rats was not altered and no mortality was observed during the study. There was no difference in the weight gain in treated and control rats. The consumption of feed was higher in SD rats during the initial 8 wk, but was slightly lower in the following period. At the beginning of the study, relative urinary volume was also significantly higher in SD rats given the test chemical in comparison with rats fed the control diet. Urinary excretion of sodium was approximately twice as high in the test chemical treated groups, but urinary pH was not affected by rat strain or treatment. All of the bladders appeared to be normal with no evidence of bladder stones, enlargement, or detectable lesions. Histological examination revealed simple hyperplasia in two rats amongst the treated animals, but no carcinomas or precancerous lesions were observed. Based on the observations made, the low observed adverse effect level (LOAEL) for the test chemical is considered to be 2500 mg/Kg/day when male rats were exposed to the test chemical for 80 weeks.

 

Repeated dose toxicity: Inhalation

The particle size distribution of the test substance was found to vary in the size of 53-500 µm, so the potential for the generation of inhalable forms is low. Moreover the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore repeated dose toxicity by inhalation route was considered to be waived.

Repeated dose toxicity: Dermal

Since the substance is used in solid form there is very low probability of the substance penerating the skin. Further the results are negative for skin sensatization and skin irritation. Therefore this end point for repeated dose toxicity by dermal route of exposure was considered for waiver.

Based on the data available for the target chemical, the test chemical is not likely to be toxic upon repeated exposure by oral route. Hence the test chemical is likely to be "not classified" for repeated exposure by oral, inhalation and dermal route as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical, the test chemical is not likely to be toxic upon repeated exposure by oral route. Hence the test chemical is likely to be "not classified" for repeated exposure by oral, inhalation and dermal route as per the criteria mentioned in CLP regulation.