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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study, comparable to guideline study with acceptable restrictions (purity of test substance not indicated).

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981
Reference Type:
publication
Title:
Teratology studies on benzothiazolesulfenamides
Author:
Stevens, M., W.
Year:
1982
Bibliographic source:
Toxicologist, 2, 73

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Pregnant Charles River COBS CD rats were used to determine the teratogenic potential of Santocure NS (N-tert-butyl-2-benzothiazolesulfenamide). Dosage levels of 0, 50, 150 or 500 mg/kg/day were administered orally by gavage as a single daily dose on days 6 through 15 of gestation. Cesarean sections were performed on all surviving dams on gestation day 20.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Santocure NS

Test animals

Species:
rat
Strain:
other: Charles River COBS CD rats
Details on test animals and environmental conditions:
All animals were individually housed, except during mating, in suspended wire-mesh cages and maintained in a temperature-, humidity-, and light-controlled environment.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: 1: 1
Duration of treatment / exposure:
Days 6-15 of gestation.
Frequency of treatment:
Daily.
Duration of test:
Days 6 to 20 of gestation.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
150 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
No. of animals per sex per dose:
25 animals per dose
Control animals:
yes
Details on study design:
Sex: female
Duration of test: Days 6 through 15 of gestation.

Examinations

Maternal examinations:
Clinical signs, body weights, Cesarean section observations.
Ovaries and uterine content:
Uterus was excised and weighed prior to removal of the fetuses, the number and location of viable and nonviable fetuses, early and late resoptions and the number of total implantations and corpora lutea were recorded
Abdominal and thoracic cavities and organs of the dams were examined for grossly evident morphological changes
Uteri from females that appeared nongravid were opened and placed in a 10% ammonium-sulfid solution for confirmation of pregnancy status
Fetal examinations:
fetuses weights were recorded
fetuses were individually examined for external malformations and variations, including the palate and eyes
each fetus was externally sexed
Ca. one-half of the fetuses were placed in Bouin's fixative for subsequent visceral examination
Ca. one-half were fixed for subsequent skeletal examination
Historical control data:
Historical control data were available.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No biologically meaningful differences in appearance or behavior in rats when compared to the control group Matting of the ventral or anogenital haircoat was noted in all four dosage groups with the greatest incidence occuring in rats in the 500 mg/kg bw/d dose group (4, 1, 2 and 10 respectively).A post-dose response of reduced activity was noted in two of these 10 rats of the highest dose group on gestation day 6 and 7. Incidental findings of hair loss and/or red matter on the nasal region were noted on several rats in the treated groups as well as the control group at various times during gestation.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
50 and 150 mg/kg bw/d: no biologically relevant differences compared to control. 500 mg/kg bw/d: very slight decrease in mean maternal body weight gain (ca. 1 -2 %) during the treatment period. However, no differences were noted in comparing the corrected gestation day 20 body weights (gestation day 20 body weight minus uterus weight) of the treated groups to the control group.
Food consumption and compound intake (if feeding study):
not specified
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 examined
Immunological findings:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
50 and 150 mg/kg bw/d: no biologically relevant differences compared to control. 500 mg/kg bw/d: very slight decrease in mean maternal body weight gain (ca. 1 -2 %) during the treatment period. However, no differences were noted in comparing the corrected gestation day 20 body weights (gestation day 20 body weight minus uterus weight) of the treated groups to the control group.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified

Maternal developmental toxicity

Description (incidence and severity):
Slight decrease were noted in the mean numbers of corpora lutea (4 %, 1%, 4 % at 50, 150 and 500 mg/kg bw/d, respectively) and total implantations in all three treatment groups (7 %, 6% and 8 % at 50, 150 and 500 mg/kg bw/d). These decreases were attributed to random occurence as ovulation and implantation occur prior to treatment. A corresponding decrease in the mean numbers of viable fetuses in these groups was not considered biologically meaningful as the values were comparable to the historical control value.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were nobiologically meaninful or statistically significant differences in the mean numbers of postimplantation loss, early resorptions, mean fetal body weight or the fetal sex distribution in the 50, 150 or 500 mg/kg/day dosage groups when compared to the control group.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There were nobiologically meaninful or statistically significant differences in the mean numbers of postimplantation loss, early resorptions, mean fetal body weight or the fetal sex distribution in the 50, 150 or 500 mg/kg/day dosage groups when compared to the control group.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There were nobiologically meaninful or statistically significant differences in the mean numbers of postimplantation loss, early resorptions, mean fetal body weight or the fetal sex distribution in the 50, 150 or 500 mg/kg/day dosage groups when compared to the control group.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There were nobiologically meaninful or statistically significant differences in the mean numbers of postimplantation loss, early resorptions, mean fetal body weight or the fetal sex distribution in the 50, 150 or 500 mg/kg/day dosage groups when compared to the control group.
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
There were no biologically meaningful differences in the total numbers of fetuses or litters with malformations in the 50, 150, or 500 mg/kg/day dosage groups when compared with the control group.
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were no biologically meaningful differences in the total numbers of fetuses or litters with malformations in the 50, 150, or 500 mg/kg/day dosage groups when compared with the control group.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no biologically meaningful differences in the total numbers of fetuses or litters with malformations in the 50, 150, or 500 mg/kg/day dosage groups when compared with the control group.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Materal observations:

Clinical signs and mortality:

No mortality occured in any of the treated animals 50 and 150 mg/kg bw/d: no biologically meaningful differences in appearance or behavior in rats when compared to the control group Matting of the ventral or anogenital haircoat was noted in all four dosage groups with the greatest incidence occuring in rats in the 500 mg/kg bw/d dose group (4, 1, 2 and 10 respectively).A post-dose response of reduced activity was noted in two of these 10 rats of the highest dose group on gestation day 6 and 7. Incidental findings of hair loss and/or red matter on the nasal region were noted on several rats in the treated groups as well as the control group at various times during gestation.

Necropsy observations at Cesarean section:

Control: 1/25 hydrometra

Clinical 50 mg/kg bw/d: 1/25 ovarian cyst 500 mg/kg bw/d: 1/25 fibrinous pleuritis and congested lungs, 1/25 hydrometra, 1/25 ovarian cyst.

Body weights:

50 and 150 mg/kg bw/d: no biologically relevant differences compared to control. 500 mg/kg bw/d: very slight decrease in mean maternal body weight gain (ca. 1 -2 %) during the treatment period. However, no differences were noted in comparing the corrected gestation day 20 body weights (gestation day 20 body weight minus uterus weight) of the treated groups to the control group.

Cesarean section observations:

50, 150, 500 mg/kg bw/d: no biologically meaningful or statistically significant differences in the mean numbers of postimplantation loss, early resorptions, mean fetal body weight or fetal sex distribution compared to control

Slight decrease were noted in the mean numbers of corpora lutea (4 %, 1%, 4 % at 50, 150 and 500 mg/kg bw/d, respectively) and total implantations in all three treatment groups (7 %, 6% amd 8 % at 50, 150 and 500 mg/kg bw/d). These decreases were attributed to random occurence as ovulation and implantation occur prior to treatment. A corresponding decrease in the mean numbers of viable fetuses in these groups was not considered biologically meaningful as the values were comparable to the historical control value.

Fetal morphological observations:

50, 150 and 500 mg/kg bw/d: no biologically meaningful differences in the total numbers of fetuses or litters with malformations compared to control.

A slight increase in the number of litters and fetuses with undeveloped renal papillae and/or distended ureters was noted in the three treated groups but was not considered biologically meaninful since this increase was within the range estabished in the historical control data. Renal papillae not developed and/or distended ureters: control: fetuses: 3(1.7%), litters: 2( 8.3 %).

50 mg/kg bw/d: fetuses: 7(4.6 %), litters: 5( 22.7 %)

150 mg/kg bw/d: fetuses: 8(5.1 %), litters: 5( 21.7 %)

500 mg/kg bw/d: fetuses: 7(4.8 %), litters: 6( 27.3 %)

Applicant's summary and conclusion

Conclusions:
Treatment with Santocure NS (N-tert-butyl-2-benzothiazolesulfenamide) did not produce a teratogenic response when administered orally to pregnant Charles River COBS CD rats at a dosage level of 500 mg/kg/day (highest applied dose) or less.
Executive summary:

Pregnant Charles River COBS CD rats were used to determine the teratogenic potential of Santocure NS (N-tert-butyl-2-benzothiazolesulfenamide). Dosage levels of 0, 50, 150 or 500 mg/kg/day were administered orally by gavage as a single daily dose on days 6 through 15 of gestation. Cesarean sections were performed on all surviving dams on gestation day 20.

Treatment with Santocure NS (N-tert-butyl-2-benzothiazolesulfenamide) did not produce a teratogenic response when administered orally to pregnant Charles River COBS CD rats at a dosage level of 500 mg/kg/day (highest applied dose) or less.