Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction: other studies
Remarks:
other: subchronic gavage study with histology of the preproduction organs
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: subchronic gavage study with histology of reproduction organs, GLP study, comparable to guideline study.
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study, comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Twenty male and twenty female Sprague-Dawley rates received 0, 100, 300 or 1000 mg N-tert-butylbenzothiazole-2-sulphenamide/kg bw by gavage. The animals were examined for mortality, overt signs of toxicity, body weight and food consumption. Clinical chemistry, haematological and urinalysis determinations were performed. At sacrifice animals were subjected to a complete gross necropsy and a microscopic examination for the control and high dose group performed.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
The animals were ca. six week of age and weighed 175-213 g for males and 130-159 g for females at the start.
Route of administration:
oral: gavage
Details on route of administration:
Dosing suspensions were perparted weekly. All animals were administered a constant volume of suspensions which was 0.5 ml of suspension per 100 g of body weight.
Vehicle:
corn oil
Details on oral exposure:
All animals were administered a constant volume of suspensions which was 0.5 ml of suspension per 100 g of body weight.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were analysed weekly using a liquid chromatographic procedure.
Duration of treatment / exposure:
90 d
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 100, 300, and 1000 mg/kg bw/d
Basis:

No. of animals per sex per dose:
20 per dose and sex
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no
Positive control:
No.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Animals in all treatment groups salivated after dosing and mid and high dose animals salivated prior to dosing or sometimes resisted dosing. High dose females exhibited urine stained abdomens. Other than the above, no clinical signs or abnormal behavior related to treatment were observed. Due to the lack of gross or microscopic findings of gastrointestinal effects, the behavioral reactions were considered to be related to poor palatability of the test material rather than a toxic response.
Mortality:
no mortality observed
Description (incidence):
All animals survived three months of exposure to the test substance.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced body weights were noted for males at the middle and highest dose groups (300 and 1,000 mg/kg/day, respectively). Most affected were the high dose group males with 13 weeks reduction at 99% statistical confidence. Middle group males were affected the final 11 out of 13 weeks, primarily at 95% statistical confidence. Body weights were unaffected for the low dose males (100 mg/kg/day) and all three female treatment groups as compared to controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Similar amounts of food were consumed by both sexes from all three treatment groups when compared to their control groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urine specific gravity was increased in males from Group 3 (1000 mg/kg bw) and females from Groups 2 and 3 (300 and 1000 mg/kg bw/d). The increased values for males and females from Group 3 were statistically significant.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The only significant changes in absolute organ weights were decreased mean brain weight in females from Group 3 (1000 mg/kg bw/d) and increased mean hepatic weight in females from Group 3 (1000 mg/kg bw/d). Organ to body weight ratios were increased in a dose related manner for all male organs for which weights were obtained (statistically significant in most instances) for Groups 2 and 3. Kidneys to body weight ratios were increased in females from Group 3 (statistically significant) as were liver to body weight ratios in females from Groups 2 and 3 (300 and 1000 mg/kg bw/d).
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross lesions associated with chemical administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no microscopic lesions with an apparent association with chemical administration.
Histopathological findings: neoplastic:
not specified
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: no adverse effects
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: decreased body weight in males, increase in urine specific gravity in females
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day (nominal)
System:
other: decreased body weight in males, increase in urine specific gravity in females
Organ:
other: decreased body weight in males, increase in urine specific gravity in females
Treatment related:
yes
Dose response relationship:
yes

Mortality: All animals survived three months of exposure to the test substance

Body Weight:

Reduced body weights were noted for males at the middle and highest dose groups (300 and 1,000 mg/kg/day, respectively). Most affected were the high dose group males with 13 weeks reduction at 99% statistical confidence. Middle group males were affected the final 11 out of 13 weeks, primarily at 95% statistical confidence. Body weights were unaffected for the low dose males (100 mg/kg/day) and all three female treatment groups as compared to controls.

Food Consumption:

Similar amounts of food were consumed by both sexes from all three treatment groups when compared to their control groups. Two exceptions were mid dose group males (300 mg/kg/day) at week 9 and high dose males (1,000 mg/kg/day) at week 1, however, these exceptions appear random and are probably not related to SANTOCURE NS exposure.

Clinical Observations:

Animals in all treatment groups salivated after dosing and mid and high dose animals salivated prior to dosing or sometimes resisted dosing. High dose females exhibited urine stained abdomens. Other than the above, no clinical signs or abnormal behavior related to treatment were observed. Due to the lack of gross or microscopic findings of gastrointestinal effects, the behavioral reactions were considered to be related to poor palatability of the test material rather than a toxic response.

Hematology and chemical data:

There were several statistically significant changes in mean values for hematologic or serum chemistry parameters. Statistically significant increases in reticulocyte counts occurred in Group 2 males (300 mg/kg bw/d) and Group 3 (1000 mg/kg bw/d) females. These values remained well within normal limits and were of no toxicological significance. Depressions of SGOT and SGPT at 100 and 1000 mg/kg bw in females were probably artifactual due to high group mean values for these enzymes in control females. When clearly abnormal values for NFOO4 and NFO15 are deleted, a minimal (p 0.05) depression was found affecting only Group 1 females (100 mg/kg bw/d). These changes were not considered to be relevant. Minimal depressions in sodium affected all dose level of females and Group 2 (300 mg/kg bw/d) males. These were within normal range and were not considered to be toxicologically relevant. The only change which may have been biologically relevant was a mild increase in the mean cholesterol value for females from Group 3 (1000 mg/kg bw /d). Urine specific gravity was increased in males from Group 3 (1000 mg/kg bw) and females from Groups 2 and 3 (300 and 1000 mg/kg bw/d). The increased values for males and females from Group 3 were statistically significant. There were increases in the occurrence of mild ketonuria in male Groups 1, 2 and 3.

Gross Pathology:

There were no gross lesions associated with chemical administration. There was a linear decrease in terminal body weights of males from Groups 1, 2 and 3. There were, however, essentially no changes in weights of females from treated groups as compared to controls. The only significant changes in absolute organ weights were decreased mean brain weight in females from Group 3 (1000 mg/kg bw/d) and increased mean hepatic weight in females from Group 3 (1000 mg/kg bw/d). Organ to body weight ratios were increased in a dose related manner for all male organs for which weights were obtained (statistically significant in most instances) for Groups 2 and 3. Kidneys to body weight ratios were increased in females from Group 3 (statistically significant) as were liver to body weight ratios in females from Groups 2 and 3 (300 and 1000 mg/kg bw/d).

Microscopic Pathology:

There were no microscopic lesions with an apparent association with chemical administration.

No test substance-related adverse effects on the reproductive organs were indicated.

Conclusions:
The lowest dose leve (100 mg/kg/day) produced no toxicologically significant changes.
Executive summary:

The test substance was administered orally by gavage to four groups of 20 male and 20 female Sprague-Dawley rats at doses of 0, 100, 300 or 1000 mg/kg/day for 3 months. All animals survived the treatment period. changes appearently associated with the test substance exposure at 1000 mg/kg7day included increased urine specific gravity and decreased body weights among males. Females at this dose level had stained abdomens, increased urine specific gravity, elevated cholesterol values, and increased liver weights. Middle dose level (300 mg/kg/day) males had decreased body weight and females had increased urine specific gravity. The lowest dose leve (100 mg/kg/day) produced no toxicologically significant changes.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Twenty male and twenty female Sprague-Dawley rates received 0, 100, 300 or 1000 mg N-tert-butylbenzothiazole-2-sulphenamide/kg bw by gavage. the animals were examined for mortality, overt signs of toxicity, body weight and food consumption. Clinical chemistry, haematological and urinalysis determinations were proformed. At sacrifice animnals were subjected to a complete gross necropsy and a microscopic examination (incl. testis, epidiymides, ovaries, uterus) for the control and high dose group performed.
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Santocure NS, purity (end of the study): 96.44 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Subchronic toxicity study.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were analysed weekly using a liquid chromatographic procedure.
Duration of treatment / exposure:
90 day.
Frequency of treatment:
Daily.
Duration of test:
90 day.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
20 per dose and sex.
Control animals:
yes, concurrent vehicle
Details on study design:
See IUCLID section 7.5.1 Monsanto 1985.

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No histological alteration of reproduction organs.

Any other information on results incl. tables

Mortality:

All animals survived three months of exposure to the test substance

Body Weight:

Reduced body weights were noted for males at the middle and highest dose groups (300 and 1,000 mg/kg/day, respectively). Most affected were the high dose group males with 13 weeks reduction at 99% statistical confidence. Middle group males were affected the final 11 out of 13 weeks, primarily at 95% statistical confidence.

Body weights were unaffected for the low dose males (100 mg/kg/day) and all three female treatment groups as compared to controls.

Food Consumption:

Similar amounts of food were consumed by both sexes from all three treatment groups when compared to their control groups. Two exceptions were mid dose group males (300 mg/kg/day) at week 9 and high dose males (1,000 mg/kg/day) at week 1, however, these exceptions appear random and are probably not related to SANTOCURE NS exposure.

Clinical Observations:

Animals in all treatment groups salivated after dosing and mid and high dose animals salivated prior to dosing or sometimes resisted dosing. High dose females exhibited urine stained abdomens. Other than the above, no clinical signs or abnormal behavior related to treatment were observed. Due to the lack of gross or microscopic findings of gastrointestinal effects, the behavioral reactions were considered to be related to poor palatability of the test material rather than a toxic response.

Hematology and chemical data:

There were several statistically significant changes in mean values for hematologic or serum chemistry parameters. Statistically significant increases in reticulocyte counts occurred in Group 2 males (300 mg/kg bw/d) and Group 3 (1000 mg/kg bw/d) females. These values remained well within normal limits and were of no toxicological significance.

Depressions of SGOT and SGPT at 100 and 1000 mg/kg bw in females were probably artifactual due to high group mean values for these enzymes in control females. When clearly abnormal values for NFOO4 and NFO15 are deleted, a minimal (p 0.05) depression was found affecting only Group 1 females (100 mg/kg bw/d). These changes were not considered to be relevant. Minimal depressions in sodium affected all dose level of females and Group 2 (300 mg/kg bw/d) males. These were within normal range and were not considered to be toxicologically relevant.

The only change which may have been biologically relevant was a mild increase in the mean cholesterol value for females from Group 3 (1000 mg/kg bw /d). Urine specific gravity was increased in males from Group 3 (1000 mg/kg bw) and females from Groups 2 and 3 (300 and 1000 mg/kg bw/d). The increased values for males and females from Group 3 were statistically significant There were increases in the occurrence of mild ketonuria in male Groups 1, 2 and 3.

Gross Pathology:

There were no gross lesions associated with chemical administration. There was a linear decrease in terminal body weights of males from Groups 1, 2 and 3. There were, however, essentially no changes in weights of females from treated groups as compared to controls. The only significant changes in absolute organ weights were decreased mean brain weight in females from Group 3 (1000 mg/kg bw/d)and increased mean hepatic weight in females from Group 3(1000 mg/kg bw/d). Organ to body weight ratios were increased in a dose related manner for all male organs for which weights were obtained (statistically significant in most instances) for Groups 2 and 3. Kidneys to body weight ratios were increased in females from Group 3 (statistically significant) as were liver to body weight ratios in females from Groups 2 and 3 (300 and 1000 mg/kg bw/d).

Microscopic Pathology:

There were no microscopic lesions with an apparent association with chemical administration.

No test substance-related adverse effects on the reproductive organs were indicated (testis, epidiymides, ovaries, uterus) up to the highest dose evaluated

Applicant's summary and conclusion

Conclusions:
No histological alteration of reproduction organs were found.
Executive summary:

Twenty male and twenty female Sprague-Dawley rates received 0, 100, 300 or 1000 mg N-tert-butylbenzothiazole-2-sulphenamide/kg bw by gavage. the animals were examined for mortality, overt signs of toxicity, body weight and food consumption. Clinical chemistry, haematological and urinalysis determinations were proformed. At sacrifice animnals were subjected to a complete gross necropsy and a microscopic examination (incl. testis, epidiymides, ovaries, uterus) for the control and high dose group performed.

No histological alteration of reproduction organs were found..