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EC number: 202-409-1 | CAS number: 95-31-8
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
- Remarks:
- Guideline GLP study with limited reporting in English (abstract, data tables etc)
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
- Remarks:
- GLP and guideline study, basic data given (abstract and tables)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- N-tert-butyl-2-benzothiazolesulfenamide was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental screening test at doses of 0, 40, 200, or 1000 mg/kg/day.
Note: The study does not report information on the following tissues/organs as required according to the guidelines: brain, spinal cord, large and small intestine, stomach, thyroid, trachea and lungs, uterus urinary bladder, lymph nodes, peripheral nerve, and bone marrow. - GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- other: 5 % gum arabic
- Duration of treatment / exposure:
- males 42 days, females from 14 days prior to mating to day 3 of lactation
- Frequency of treatment:
- daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Vehicle control
- Dose / conc.:
- 40 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 13 per dose per sex
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- Mortality, clinical signs, clinical chemistry and haematology.
- Sacrifice and pathology:
- Gross pathology and histopathology.
- Other examinations:
- Gestation index, implantation index, delivery index, birth index, live birth index, sex ration, viability index.
Day 4 of lactation: number of pups alive, viability index, pup weights in grams. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In males and females temporary salivation after each administration at 1000 mg/kg/day.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In males suppresion of food consumption and body weight gain at 1000 mg/kg/day.
In females food consumption was decreased prior mating and along with slight suppression of body weight gain during pregnancy at 1000 mg/kg/bw. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- In males suppresion of food consumption and body weight gain at 1000 mg/kg/day.
In females food consumption was decreased prior mating and along with slight suppression of body weight gain during pregnancy at 1000 mg/kg/bw. - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In males hemoglobin and hemocrit values were slightly decreased and hemolytic anemia was induced at 1000 mg/kg bw.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In males slight increase in the total bilirubin concentration and dose-dependent increase in the deposition of hemosiderin in the spleen at 200 and 1000 mg/kg bw.
- Urinalysis findings:
- not specified
- 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):
- In males increase in absolute and relative kidney weights and increase in relative liver weights at 1000 mg/kg/day.
In females slight increase in the relative kidney weights (not dose dependent) and slight increase in the relative kidney weights. - Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- In males increase in eosinophilic bodies in the kidney, however the incidences was increased but not the severity compared to control. hypertrophy of hepatocytes in the central zone. Decrease in fatty change of hepatocytes in the periportal zone.
In females at autopsy on postpartum day 4, slight vacuolar degeneration in the proximal tubules of kidney was observed, slight hypertrophy of hepatocytes in the central zone and depostion of brown pigment in the spleen (tended to increase but in many cases comparable to control group). - Histopathological findings: neoplastic:
- not examined
- Dose descriptor:
- NOAEL
- Effect level:
- 40 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: no effects
- Dose descriptor:
- LOAEL
- Effect level:
- 200 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: slight histopathological changes in kidney and in the liver
- Critical effects observed:
- no
- Conclusions:
- NOAEL = 40 mg/kg bw/day (males/females)
LOAEL = 200 mg/kg/day (males/females)
On review of the wider category dataset the LOAEL of 40 mg/kg bw/day set by the authors appears to be based on adaptive or effects of little toxicological relevance, therefore a NOAEL of 40 mg/kg bw/day is suggested for male animals. - Executive summary:
N-tert-butyl-2-benzothiazolesulfenamide was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental screening test at doses of 0, 40, 200, or 1000 mg/kg/day. The NOAEL in females was 40 mg/kg/day. In males the LOAEL was reported by the study authors as 40 mg/kg bw based on an increase in eosinophilic bodies in the kidney.
Males:
40 mg/kg bw/day
increase in eosinophilic bodies in the kidney, however the incidences was increased but not the severity compared to control (see table 1)
200 mg/kg bw/day
temporary salivation after each administration of test substance
increase in eosinophilic bodies in the kidney, however the incidences was increased but not the severity compared to control (see table 1)
slight hypertrophy of hepatocytes in the central zone
slight increase in the total bilirubin concentration and dose-dependent increase in the deposition of hemosiderin in the spleen
1000 mg/kg bw/day
suppresion of food consumption and body weight gain
temporary salivation after each administration of test substance
increase in eosinophilic bodies in the kidney, however the incidences was increased but not the severity compared to control (see table 1)
increase in absolute and relative kidney weights
hypertrophy of hepatocytes in the central zone
increase in relative liver weights
decrease in fatty change of hepatocytes in the periportal zone
slight increase in the total bilirubin concentration and dose-dependent increase in the deposition of hemosiderin in the spleen
hemoglobin and hemocrit values were slightly decreased and hemolytic anemia was induced
slight increase in total cholesterol concentration
Females:
40 mg/kg bw/day
no effects
200 mg/kg bw/day
temporary salivation after each administration
at autopsy on postpartum day 4, slight vacuolar degeneration in the proximal tubules of kidney was observed (see table 1)
slight increase in the relative kidney weights (not dose dependent)
slight hypertrophy of hepatocytes in the central zone
1000 mg/kg bw/day
temporary salivation after each administration
food consumption was decreased prior mating and along with slight suppression of body weight gain during pregnancy
at autopsy on postpartum day 4, slight vacuolar degeneration in the proximal tubules of kidney was observed
slight increase in the relative kidney weights
slight hypertrophy of hepatocytes in the central zone
increase in absolute and relative liver weights
depostion of brown pigment in the spleen (tended to increase but in many cases comparable to control group)
Table 1: Body weights of male rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Days of administration
| Dose | |||
| 0 | 40 | 200 | 1000 | |
| 1 (initial weight) | 281.4 ± 8.6 | 281.8 ± 9.4 | 281.9 ± 9.9 | 281.9 ± 9.0 |
| 8 | 327.1 ± 8.6 | 333.7 ± 16.4 | 336.2 ± 17.2 | 317.3 ± 17.8 |
| 15 | 327.2 ± 18.2 | 376.4 ± 22.0 | 385.1 ± 21.1 | 357.0 ± 24.2 |
| 22 | 401.3 ± 23.7 | 410.3 ± 27.7 | 414.9 ± 22.0 | 385.6 ± 30.2 |
| 29 | 430.6 ± 27.5 | 440.8 ± 33.0 | 442.5 ± 24.5 | 411.5 ± 36.1 |
| 36 | 458.6 ± 32.8 | 469.2 ± 36.0 | 471.1 ± 27.3 | 431.9 ± 40.6 |
| 42 | 479.4 ± 37.7 | 488.2 ± 37.7 | 487.2 ± 31.3 | 445.8 ± 44.5 |
Values are expressed as Mean ± S.D. in grams – 13 animals used in each group throughout the study
Table 2: Body weights of female rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Days of |
| Dose (mg/kg) |
| |
administration (pre-mating period) | 0 | 40 | 200 | 1000 |
1 (Init. wt.) | 190.2 ± 7.2 (13) | 189.5 ± 6.4 (13) | 189.7 ± 6.8 (13) | 190.0 ± 5.8 (13) |
8 | 211.2 ± 8.2 (13) | 208.2 ± 10.0 (13) | 211.4 ± 8.1 (13) | 207.3 ± 7.6 (13) |
15 | 229.8 ± 11.8 (13) | 225.9 ± 11.7 (13) | 229.5 ± 10.9 (13) | 222.5 ± 8.6 (13) |
Days of pregnancy 0 |
234.2 ± 13.5 (10) |
236.9 ± 21.0 (7) |
239.0 ± 11.5 (13) |
233.5 ± 16.4 (9) |
7 | 272.2 ± 17.1 (10) | 273.8 ± 29.3 (7) | 276.0 ± 16.2 (13) | 258.9 ± 19.0 (9) |
14 | 308.1 ± 18.1 (10) | 311.3 ± 34.9 (7) | 312.5 ± 17.7 (13) | 290.4 ± 22.6 (9) |
20 | 374.1 ± 23.4 (10) | 380.4 ± 41.4 (7) | 385.1 ± 26.1 (13) | 343.0 ± 40.4 (9) |
Days of lactation 0 |
284.2 ± 23.2 (10) |
276.6 ± 37.3 (6) |
283.6 ± 26.2 (13) |
262.2 ± 27.4 (8) |
4 | 302.5 ± 14.1 (10) | 308.1 ± 29.3 (6) | 301.5 ± 20.3 (13) | 284.9 ± 34.6 (8) |
Values are expressed as Mean ± S.D. in grams.
Parenthesis indicates number of animals
Table 3: Food consumption of male rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Days of |
| Dose (mg/kg) |
| |
administration | 0 | 40 | 200 | 1000 |
1 – 8 | 202.8 ± 22.7 | 205.7 ± 10.9 | 211.1 ± 13.3 | 181.9 ± 15.5** |
8 – 15 | 202.9 ± 19.4 | 200.1 ± 11.1 | 215.4 ± 13.5 | 191.1 ± 21.3 |
29 – 36 | 197.4 ± 20.4 | 205.2 ± 21.8 | 211.4 ± 18.5 | 192.7 ± 25.4 |
36 – 42 | 174.9 ± 18.6 | 177.9 ± 19.6 | 179.6 ± 14.3 | 165.8 ± 20.3 |
Values are expressed as Mean ± S.D. in grams – 13 animals used in each group throughout the study
**: significant difference from control, p<0.01
Table 4: Food consumption of female rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Days of Dose (mg/kg) administration 0 40 200 1000
(pre-mating period)
1 – 8 132.5 ± 7.3 (13) 130.8 ± 8.9 (13) 133.2 ± 9.3 (13) 116.7 ± 8.0** (13)
8 – 15 137.3 ± 10.8 (13) 134.1 ± 12.9 (13) 136.8 ± 11.7 (13) 124.7 ± 12.5* (13)
Days of pregnancy
0 – 7 166.8 ± 16.9 (10) 165.3 ± 29.1 (7) 164.2 ± 16.5 (13) 133.4 ± 25.8* (9)
7 – 14 177.9 ± 15.2 (10) 180.9 ± 29.4 (7) 177.9 ± 15.2 (13) 161.2 ± 16.3 (9)
14 – 20 140.9 ± 8.8 (10) 138.3 ± 9.8 (7) 143.3 ± 11.7 (13) 122.4 ± 16.3* (9)
Days of lactation
0 – 4 122.3 ± 21.9 (10) 117.6 ± 15.0 (6) 108.8 ± 25.8 (13) 121.2 ± 25.3 (8)
Values are expressed as Mean ± S.D. in grams
Parenthesis indicates number of animals
*: significant difference from control, p<0.05
**: significant difference from control, p<0.01
Table 5: Hematological findings of male rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
| 0 | 40 | 200 | 1000 |
|
| Red Blood Cells |
|
|
Count (X104/mm3) | 805 ± 35 | 814 ± 40 | 807 ± 31 | 774 ± 40 |
Hemoglobin (g/dl) | 15.4 ± 0.6 | 15.5 ± 0.7 | 15.3 ± 0.5 | 14.5 ± 0.4** |
Hematocrit (%) | 44.4 ± 1.6 | 44.7 ± 1.9 | 43.7 ± 1.7 | 41.6 ± 1.6** |
MCV (µm 3) | 55.2 ± 1.7 | 55.0 ± 2.1 | 54.2 ± 1.1 | 53.7 ± 1.1 |
MCH (pg) | 19.1 ± 0.7 | 19.0 ± 0.8 | 18.9 ± 0.4 | 18.7 ± 0.5 |
MCHC (%) | 34.6 ± 0.6 | 34.6 ± 0.4 White Blood Cells | 35.0 ± 0.5 | 34.8 ± 0.5 |
Count (X102/mm3) | 116 ± 20 | 111 ± 23 | 101 ± 19 | 86 ± 28** |
Band neutrophil (%) | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
Segmented neutrophil (%) | 10 ± 4 | 10 ± 5 | 15 ± 10 | 16 ± 11 |
Eosinophil (%) | 0 ± 1 | 1 ± 1 | 1 ± 1 | 1 ± 1 |
Basophil (%) | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
Monocyte (%) | 2 ± 2 | 2 ± 2 | 1 ± 1 | 2 ± 2 |
Lymphocyte (%) | 87 ± 5 | 87 ± 6 Platelet | 83 ± 10 | 81 ± 11 |
Count (X104/mm3) | 114.1 ± 8.2 | 112.5 ± 10.1 | 111.9 ± 8.9 | 115.8 ± 8.1 |
Values are expressed as Mean ± S.D. – 13 animals used in each group throughout the study
**: significant difference from control, p<0.01
Table 6: Blood chemical findings of male rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
| Dose (mg/kg) 0 | 40 | 200 | 1000 |
Total protein (g/dl) | 5.5 ± 0.3 | 5.6 ± 0.3 | 5.8 ± 0.2 | 5.7 ± 0.4 |
Albumin (g/dl) | 2.8 ± 0.2 | 2.9 ± 0.3 | 3.0 ± 0.1 | 3.0 ± 0.1 |
A/C | 1.05 ± 0.08 | 1.06 ± 0.15 | 1.08 ± 0.12 | 1.10 ± 0.15 |
BUN (mg/dl) | 17 ± 2 | 17 ± 2 | 17 ± 2 | 18 ± 2 |
Creatinine (mg/dl) | 0.7 ± 0.1 | 0.7 ± 0.1 | 0.7 ± 0.0 | 0.7 ± 0.1 |
Glucose (mg/dl) | 137 ± 13 | 157 ± 14** | 141 ± 12 | 120 ± 15** |
Total cholesterol (mg/dl) | 59 ± 13 | 58 ± 11 | 59 ± 8 | 70 ± 12* |
Total bilirubin (mg/dl) | 0.07 ± 0.02 | 0.09 ± 0.02 | 0.09 ± 0.02** | 0.09 ± 0.02** |
Na (mEq/l) | 144.5 ± 1.1 | 144.4 ± 0.9 | 144.6 ± 0.9 | 145.6 ± 0.7* |
K (mEq/l) | 3.77 ± 0.23 | 3.76 ± 0.13 | 3.83 ± 0.22 | 3.91 ± 0.2 |
Cl (mEq/l) | 106.6 ± 1.4 | 105.8 ± 0.9 | 105.9 ± 1.0 | 106.0 ± 1.2 |
Ca (mg/dl) | 8.6 ± 0.4 | 8.6 ± 0.5 | 8.7 ± 0.2 | 8.9 ± 0.2 |
Inorg. phos. (mg/dl) | 6.2 ± 0.6 | 6.2 ± 0.5 | 5.7 ± 0.4 | 5.8 ± 0.5 |
ALP (U/l) | 199 ± 41 | 218 ± 54 | 220 ± 38 | 205 ± 65 |
GOT (U/l) | 58 ± 7 | 59 ± 7 | 60 ± 6 | 59 ± 10 |
γ. GTP (U/l) | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
Values are expressed as Mean ± S.D. – 13 animals used in each group throughout the study
*: significant difference from control, p<0.05
**: significant difference from control, p<0.01
Table 7: Absolute and relative organ weights of rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Sex | Dose (mg/kg bw/day) | 0 |
| 40 |
| 200 |
| 1000 |
|
| |||
Male
| Final body weight (g) | 447.2 ± 35.0 | (13) | 458.4 ± 36.1 | (13) | 455.9 ± 29.2 | (13) | 416.5 ± 42.4 | (13) |
| |||
|
|
|
|
|
|
|
|
|
|
| |||
| Liver (g) | 12.57 ± 1.73a | (13) | 14.21 ± 1.78 | (13) | 13.65 ± 0.98 | (13) | 13.41 ± 1.53 | (13) |
| |||
|
| 2.80 ± 0.21b |
| 3.09 ± 0.22** |
| 3.00 ± 0.15* |
| 3.22 ± 0.22** |
|
| |||
|
|
|
|
|
|
|
|
|
|
| |||
| Kidneys (g) | 2.94 ± 0.32 | (13) | 3.03 ± 0.26 | (13) | 3.16 ± 0.27 | (13) | 3.27 ± 0.25* | (13) |
| |||
|
| 0.66 ± 0.06 |
| 0.66 ± 0.05 |
| 0.69 ± 0.05 |
| 0.79 ± 0.06** |
|
| |||
|
|
|
|
|
|
|
|
|
|
| |||
| Spleen (g) | 0.77 ± 0.11 | (13) | 0.76 ± 0.07 | (13) | 0.76 ± 0.09 | (13) | 0.73 ± 0.10 | (13) |
| |||
|
| 0.17 ± 0.02 |
| 0.17 ± 0.02 |
| 0.17 ± 0.02 |
| 0.18 ± 0.02 |
|
| |||
Thymus (mg)
|
389.8 ± 122.5 86.8 ± 25.7
|
(13)
|
370.1 ± 55.2 80.8 ± 10.8
|
(13)
|
375.7 ± 67.3 82.5 ± 14.9
|
(13)
|
313.5 ± 97.5 74.3 ± 18.3
|
(13)
| |||||
Testes (g) | 3.04 ± 0.29 | (13) | 3.01 ± 0.21 | (13) | 3.02 ± 0.38 | (13) | 3.14 ± 0.21 | (13) | |||||
| 0.68 ± 0.06 |
| 0.66 ± 0.07 |
| 0.66 ± 0.07 |
| 0.76 ± 0.09* |
| |||||
Epididymides (g) |
1.10 ± 0.12 |
(13) |
1.04 ± 0.10 |
(13) |
1.07 ± 0.13 |
(13) |
1.06 ± 0.10 |
(13) | |||||
| 0.24 ± 0.03 |
| 0.23 ± 0.03 |
| 0.23 ± 0.03 |
| 0.26 ± 0.04 |
| |||||
Final body weight (g) | 302.5 ± 14.1 | (10) | 308.1 ± 29.3 | (6) | 301.5 ± 20.3 | (13) | 284.9 ± 34.6 | (8) | |||||
Liver (g) |
12.87 ± 1.01 |
(10) |
13.16 ± 1.49 | (6) |
14.15 ± 2.26 |
(13) |
14.59 ± 3.05 | (8) | |||||
| 4.26 ± 0.38 |
| 4.27 ± 0.29 |
| 4.70 ± 0.67 |
| 5.10 ± 0.68* |
| |||||
Kidneys (g) |
2.09 ± 0.24 |
(10) |
2.00 ± 0.28 | (6) |
2.14 ± 0.24 |
(13) |
2.09 ± 0.11 | (8) | |||||
Female | 0.69 ± 0.08 |
| 0.65 ± 0.07 |
| 0.71 ± 0.07 |
| 0.74 ± 0.06 |
| |||||
Spleen (g) |
0.66 ± 0.09 |
(10) |
0.60 ± 0.10 | (6) |
0.56 ± 0.07 |
(13) |
0.57 ± 0.11 | (8) | |||||
| 0.22 ± 0.03
|
| 0.19 ± 0.01
|
| 0.19 ± 0.02
|
| 0.20 ± 0.03
|
| |||||
Thymus (mg) | 190.5 ± 49.5 | (10) | 168.7 ± 39.2 | (6) | 177.5 ± 76.6 | (13) | 154.7 ± 68.4 | (8) | |||||
| 62.8 ± 15.0 |
| 55.1 ± 13.4 |
| 58.5 ± 24.5 |
| 52.6 ± 19.5 |
| |||||
Values are expressed as Mean ± S.D.
Parenthesis indicates number of animals
a: absolute weight
b: relative weight (g or mg per 100 g body weight)
*: significant difference from control, p<0.05
**: significant difference from control, p<0.01
Table 8: Histopathological findings of rats treated with TBBS in the combined repeat dose and reproductive/developmental toxicity screening test
| Organ findings, grade and number of animals | Sex | male | female | ||||||
| Dose (mg/kg bw/d) | 0 | 40 | 200 | 1000 | 0 | 40 | 200 | 1000 | |
| Kidney | |||||||||
| Number of animals evaluated | 13 | 13 | 13 | 13 | 13 | 13 | 13 | 13 | |
| Eosinophilic body | total | 6 | 13** | 13** | 13** | 0 | 0 | 0 | 0 |
| +/- | 2 | 5 | 6 | 1 | |||||
| + | 1 | 7 | 5 | 2 | |||||
| ++ | 3 | 1 | 1 | 10 | |||||
| +++ | 0 | 0 | 1 | 0 | |||||
Basophilic tubule cortex | total | 9 | 9 | 7 | 8 | 4 | 3 | 6 | 1 |
| ± | 7 | 9 | 5 | 8 | 3 | 3 | 6 | 1 | |
| + | 2 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | |
| ++ | 0 | 0 | 1 | 0 | |||||
Degeneration, vacuolar, proximal tubule | total | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 3 |
| ± | 0 | 0 | 3 | 1 | |||||
| + | 0 | 0 | 0 | 2 | |||||
**significant difference from control, p<0.01 (Mann-Whitney U test)
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 997
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- N-tert-butyl-2-benzothiazolesulfenamide was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental screening test at doses of 0, 40, 200, or 1000 mg/kg/day.
Note: The study does not report information on the following tissues/organs as required according to the guidelines: brain, spinal cord, large and small intestine, stomach, thyroid, trachea and lungs, uterus urinary bladder, lymph nodes, peripheral nerve, and bone marrow. - GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- N-tert-butylbenzothiazole-2-sulphenamide
- EC Number:
- 202-409-1
- EC Name:
- N-tert-butylbenzothiazole-2-sulphenamide
- Cas Number:
- 95-31-8
- Molecular formula:
- C11H14N2S2
- IUPAC Name:
- N-(1,3-benzothiazol-2-ylsulfanyl)-2-methylpropan-2-amine
- Details on test material:
- purity: 96.4%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crj:CD SPF
- Details on species / strain selection:
- Rats of this strain were chosen because they are the most commonly used in reproductive and developmental toxicity studies and historical control data are available.
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 5% gum arabic
- Details on mating procedure:
- No data.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Males 42 days, females 38 days (from 14 days prior to mating to day 3 of lactation).
- Frequency of treatment:
- Daily.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 40 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 13 animals per dose and sex.
- Control animals:
- yes
- Positive control:
- None.
Examinations
- Parental animals: Observations and examinations:
- Number of mated pairs, number of copulated pairs, copulation index, number of pregnant animals, fertility index, pairing days until copulation.
- Oestrous cyclicity (parental animals):
- Frquency of vaginal estrus.
- Litter observations:
- Number of pregnant females, number of pregnant females with pups alive, gestation index, number of corpora lutea, number of implantation sites, implantation index, number of pups born, delivery index, number of pups alive, birth index, live birth index, pup weights in grams.
- Postmortem examinations (parental animals):
- Gross pathology and histopathology. See also IUCLID section 7.5.1 MHJW, 1997.
- Reproductive indices:
- Gestation index, implantation index, delivery index, birth index, live birth index, sex ration, viability index.
- Offspring viability indices:
- Day 4 of lactation: number of pups alive, viability index, pup weights in grams.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In males and females temporary salivation after each administration at 1000 mg/kg/day.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In males suppresion of food consumption and body weight gain at 1000 mg/kg/day.
In females food consumption was decreased prior mating and along with slight suppression of body weight gain during pregnancy at 1000 mg/kg/bw. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- In males suppresion of food consumption and body weight gain at 1000 mg/kg/day.
In females food consumption was decreased prior mating and along with slight suppression of body weight gain during pregnancy at 1000 mg/kg/bw. - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In males hemoglobin and hemocrit values were slightly decreased and hemolytic anemia was induced at 1000 mg/kg bw.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In males slight increase in the total bilirubin concentration and dose-dependent increase in the deposition of hemosiderin in the spleen at 200 and 1000 mg/kg bw.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- In males increase in eosinophilic bodies in the kidney, however the incidences was increased but not the severity compared to control. hypertrophy of hepatocytes in the central zone. Decrease in fatty change of hepatocytes in the periportal zone.
In females at autopsy on postpartum day 4, slight vacuolar degeneration in the proximal tubules of kidney was observed, slight hypertrophy of hepatocytes in the central zone and depostion of brown pigment in the spleen (tended to increase but in many cases comparable to control group). - Histopathological findings: neoplastic:
- not examined
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Systemic
- Effect level:
- 40 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no effects
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- Systemic
- Effect level:
- 40 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: increase in eosinophilic bodies in the kidney
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- systemic
- Effect level:
- 200 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: slight histopathological changes in kidney and in the liver
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- fertility
- Effect level:
- 200 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects
Target system / organ toxicity (P0)
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 200 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- N-tert-butyl-2-benzothiazolesulfenamide at the dose levels applied did not demonstrate teratogenicity.
- Histopathological findings:
- no effects observed
- Description (incidence and severity):
- N-tert-butyl-2-benzothiazolesulfenamide at the dose levels applied did not demonstrate teratogenicity.
- Other effects:
- no effects observed
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- no effects observed
Details on results (F1)
No dose related abnormalities were observed with regard to parturition and lactation. There were no adverse effects on viability, the sex ratio and body weights of pups in any N-tert-butyl-2-benzothiazolesulfenamide treated group.
N-tert-butyl-2-benzothiazolesulfenamide at the dose levels applied did not demonstrate teratogenicity.
The no effect level (NOEL) of N-tert-butyl-2-benzothiazolesulfenamide for reproductive and developmental toxicity was 200 mg/kg/day in males and females.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- > 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects on viability, the sex ratio and body weights of pups in any of the treated animals. TBBS at the dose levels applied did not demonstrate teratogenicity.
- Remarks on result:
- other: 1000 mg/kg bw was the highest applied dose.
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Males:
40 mg/kg bw/day
increase in eosinophilic bodies in the kidney, however the incidences was increased but not the severity compared to control (see table 1)
200 mg/kg bw/day
temporary salivation after each administration of test substance
increase in eosinophilic bodies in the kidney, however the incidences was increased but not the severity compared to control (see table 1)
slight hypertrophy of hepatocytes in the central zone
slight increase in the total bilirubin concentration and dose-dependent increase in the deposition of hemosiderin in the spleen
1000 mg/kg bw/day
suppresion of food consumption and body weight gain
temporary salivation after each administration of test substance
increase in eosinophilic bodies in the kidney, however the incidences was increased but not the severity compared to control (see table 1)
increase in absolute and relative kidney weights
hypertrophy of hepatocytes in the central zone
increase in relative liver weights
decrease in fatty change of hepatocytes in the periportal zone
slight increase in the total bilirubin concentration and dose-dependent increase in the deposition of hemosiderin in the spleen
hemoglobin and hemocrit values were slightly decreased and hemolytic anemia was induced
slight increase in total cholesterol concentration
Females:
40 mg/kg bw/day
no effects
200 mg/kg bw/day
temporary salivation after each administration
at autopsy on postpartum day 4, slight vacuolar degeneration in the proximal tubules of kidney was observed (see table 1)
slight increase in the relative kidney weights (not dose dependent)
slight hypertrophy of hepatocytes in the central zone
1000 mg/kg bw/day
temporary salivation after each administration
food consumption was decreased prior mating and along with slight suppression of body weight gain during pregnancy
at autopsy on postpartum day 4, slight vacuolar degeneration in the proximal tubules of kidney was observed
slight increase in the relative kidney weights
slight hypertrophy of hepatocytes in the central zone
increase in absolute and relative liver weights
depostion of brown pigment in the spleen (tended to increase but in many cases comparable to control group)
Table 1: Body weights of male rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Days of administration
| Dose | |||
| 0 | 40 | 200 | 1000 | |
| 1 (initial weight) | 281.4 ± 8.6 | 281.8 ± 9.4 | 281.9 ± 9.9 | 281.9 ± 9.0 |
| 8 | 327.1 ± 8.6 | 333.7 ± 16.4 | 336.2 ± 17.2 | 317.3 ± 17.8 |
| 15 | 327.2 ± 18.2 | 376.4 ± 22.0 | 385.1 ± 21.1 | 357.0 ± 24.2 |
| 22 | 401.3 ± 23.7 | 410.3 ± 27.7 | 414.9 ± 22.0 | 385.6 ± 30.2 |
| 29 | 430.6 ± 27.5 | 440.8 ± 33.0 | 442.5 ± 24.5 | 411.5 ± 36.1 |
| 36 | 458.6 ± 32.8 | 469.2 ± 36.0 | 471.1 ± 27.3 | 431.9 ± 40.6 |
| 42 | 479.4 ± 37.7 | 488.2 ± 37.7 | 487.2 ± 31.3 | 445.8 ± 44.5 |
Values are expressed as Mean ± S.D. in grams – 13 animals used in each group throughout the study
Table 2: Body weights of female rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Days of |
| Dose (mg/kg) |
| |
administration (pre-mating period) | 0 | 40 | 200 | 1000 |
1 (Init. wt.) | 190.2 ± 7.2 (13) | 189.5 ± 6.4 (13) | 189.7 ± 6.8 (13) | 190.0 ± 5.8 (13) |
8 | 211.2 ± 8.2 (13) | 208.2 ± 10.0 (13) | 211.4 ± 8.1 (13) | 207.3 ± 7.6 (13) |
15 | 229.8 ± 11.8 (13) | 225.9 ± 11.7 (13) | 229.5 ± 10.9 (13) | 222.5 ± 8.6 (13) |
Days of pregnancy 0 |
234.2 ± 13.5 (10) |
236.9 ± 21.0 (7) |
239.0 ± 11.5 (13) |
233.5 ± 16.4 (9) |
7 | 272.2 ± 17.1 (10) | 273.8 ± 29.3 (7) | 276.0 ± 16.2 (13) | 258.9 ± 19.0 (9) |
14 | 308.1 ± 18.1 (10) | 311.3 ± 34.9 (7) | 312.5 ± 17.7 (13) | 290.4 ± 22.6 (9) |
20 | 374.1 ± 23.4 (10) | 380.4 ± 41.4 (7) | 385.1 ± 26.1 (13) | 343.0 ± 40.4 (9) |
Days of lactation 0 |
284.2 ± 23.2 (10) |
276.6 ± 37.3 (6) |
283.6 ± 26.2 (13) |
262.2 ± 27.4 (8) |
4 | 302.5 ± 14.1 (10) | 308.1 ± 29.3 (6) | 301.5 ± 20.3 (13) | 284.9 ± 34.6 (8) |
Values are expressed as Mean ± S.D. in grams.
Parenthesis indicates number of animals
Table 3: Food consumption of male rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Days of |
| Dose (mg/kg) |
| |
administration | 0 | 40 | 200 | 1000 |
1 – 8 | 202.8 ± 22.7 | 205.7 ± 10.9 | 211.1 ± 13.3 | 181.9 ± 15.5** |
8 – 15 | 202.9 ± 19.4 | 200.1 ± 11.1 | 215.4 ± 13.5 | 191.1 ± 21.3 |
29 – 36 | 197.4 ± 20.4 | 205.2 ± 21.8 | 211.4 ± 18.5 | 192.7 ± 25.4 |
36 – 42 | 174.9 ± 18.6 | 177.9 ± 19.6 | 179.6 ± 14.3 | 165.8 ± 20.3 |
Values are expressed as Mean ± S.D. in grams – 13 animals used in each group throughout the study
**: significant difference from control, p<0.01
Table 4: Food consumption of female rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Days of Dose (mg/kg) administration 0 40 200 1000
(pre-mating period)
1 – 8 132.5 ± 7.3 (13) 130.8 ± 8.9 (13) 133.2 ± 9.3 (13) 116.7 ± 8.0** (13)
8 – 15 137.3 ± 10.8 (13) 134.1 ± 12.9 (13) 136.8 ± 11.7 (13) 124.7 ± 12.5* (13)
Days of pregnancy
0 – 7 166.8 ± 16.9 (10) 165.3 ± 29.1 (7) 164.2 ± 16.5 (13) 133.4 ± 25.8* (9)
7 – 14 177.9 ± 15.2 (10) 180.9 ± 29.4 (7) 177.9 ± 15.2 (13) 161.2 ± 16.3 (9)
14 – 20 140.9 ± 8.8 (10) 138.3 ± 9.8 (7) 143.3 ± 11.7 (13) 122.4 ± 16.3* (9)
Days of lactation
0 – 4 122.3 ± 21.9 (10) 117.6 ± 15.0 (6) 108.8 ± 25.8 (13) 121.2 ± 25.3 (8)
Values are expressed as Mean ± S.D. in grams
Parenthesis indicates number of animals
*: significant difference from control, p<0.05
**: significant difference from control, p<0.01
Table 5: Hematological findings of male rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
| 0 | 40 | 200 | 1000 |
|
| Red Blood Cells |
|
|
Count (X104/mm3) | 805 ± 35 | 814 ± 40 | 807 ± 31 | 774 ± 40 |
Hemoglobin (g/dl) | 15.4 ± 0.6 | 15.5 ± 0.7 | 15.3 ± 0.5 | 14.5 ± 0.4** |
Hematocrit (%) | 44.4 ± 1.6 | 44.7 ± 1.9 | 43.7 ± 1.7 | 41.6 ± 1.6** |
MCV (µm 3) | 55.2 ± 1.7 | 55.0 ± 2.1 | 54.2 ± 1.1 | 53.7 ± 1.1 |
MCH (pg) | 19.1 ± 0.7 | 19.0 ± 0.8 | 18.9 ± 0.4 | 18.7 ± 0.5 |
MCHC (%) | 34.6 ± 0.6 | 34.6 ± 0.4 White Blood Cells | 35.0 ± 0.5 | 34.8 ± 0.5 |
Count (X102/mm3) | 116 ± 20 | 111 ± 23 | 101 ± 19 | 86 ± 28** |
Band neutrophil (%) | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
Segmented neutrophil (%) | 10 ± 4 | 10 ± 5 | 15 ± 10 | 16 ± 11 |
Eosinophil (%) | 0 ± 1 | 1 ± 1 | 1 ± 1 | 1 ± 1 |
Basophil (%) | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
Monocyte (%) | 2 ± 2 | 2 ± 2 | 1 ± 1 | 2 ± 2 |
Lymphocyte (%) | 87 ± 5 | 87 ± 6 Platelet | 83 ± 10 | 81 ± 11 |
Count (X104/mm3) | 114.1 ± 8.2 | 112.5 ± 10.1 | 111.9 ± 8.9 | 115.8 ± 8.1 |
Values are expressed as Mean ± S.D. – 13 animals used in each group throughout the study
**: significant difference from control, p<0.01
Table 6: Blood chemical findings of male rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
| Dose (mg/kg) 0 | 40 | 200 | 1000 |
Total protein (g/dl) | 5.5 ± 0.3 | 5.6 ± 0.3 | 5.8 ± 0.2 | 5.7 ± 0.4 |
Albumin (g/dl) | 2.8 ± 0.2 | 2.9 ± 0.3 | 3.0 ± 0.1 | 3.0 ± 0.1 |
A/C | 1.05 ± 0.08 | 1.06 ± 0.15 | 1.08 ± 0.12 | 1.10 ± 0.15 |
BUN (mg/dl) | 17 ± 2 | 17 ± 2 | 17 ± 2 | 18 ± 2 |
Creatinine (mg/dl) | 0.7 ± 0.1 | 0.7 ± 0.1 | 0.7 ± 0.0 | 0.7 ± 0.1 |
Glucose (mg/dl) | 137 ± 13 | 157 ± 14** | 141 ± 12 | 120 ± 15** |
Total cholesterol (mg/dl) | 59 ± 13 | 58 ± 11 | 59 ± 8 | 70 ± 12* |
Total bilirubin (mg/dl) | 0.07 ± 0.02 | 0.09 ± 0.02 | 0.09 ± 0.02** | 0.09 ± 0.02** |
Na (mEq/l) | 144.5 ± 1.1 | 144.4 ± 0.9 | 144.6 ± 0.9 | 145.6 ± 0.7* |
K (mEq/l) | 3.77 ± 0.23 | 3.76 ± 0.13 | 3.83 ± 0.22 | 3.91 ± 0.2 |
Cl (mEq/l) | 106.6 ± 1.4 | 105.8 ± 0.9 | 105.9 ± 1.0 | 106.0 ± 1.2 |
Ca (mg/dl) | 8.6 ± 0.4 | 8.6 ± 0.5 | 8.7 ± 0.2 | 8.9 ± 0.2 |
Inorg. phos. (mg/dl) | 6.2 ± 0.6 | 6.2 ± 0.5 | 5.7 ± 0.4 | 5.8 ± 0.5 |
ALP (U/l) | 199 ± 41 | 218 ± 54 | 220 ± 38 | 205 ± 65 |
GOT (U/l) | 58 ± 7 | 59 ± 7 | 60 ± 6 | 59 ± 10 |
γ. GTP (U/l) | 0 ± 0 | 0 ± 0 | 0 ± 0 | 0 ± 0 |
Values are expressed as Mean ± S.D. – 13 animals used in each group throughout the study
*: significant difference from control, p<0.05
**: significant difference from control, p<0.01
Table 7: Absolute and relative organ weights of rats treated orally with N-tert-butyl-2-benzothiazolesulfenamide in the combined repeat dose and reproductive/developmental toxicity screening test
Sex | Dose (mg/kg bw/day) | 0 |
| 40 |
| 200 |
| 1000 |
|
| |||
Male
| Final body weight (g) | 447.2 ± 35.0 | (13) | 458.4 ± 36.1 | (13) | 455.9 ± 29.2 | (13) | 416.5 ± 42.4 | (13) |
| |||
|
|
|
|
|
|
|
|
|
|
| |||
| Liver (g) | 12.57 ± 1.73a | (13) | 14.21 ± 1.78 | (13) | 13.65 ± 0.98 | (13) | 13.41 ± 1.53 | (13) |
| |||
|
| 2.80 ± 0.21b |
| 3.09 ± 0.22** |
| 3.00 ± 0.15* |
| 3.22 ± 0.22** |
|
| |||
|
|
|
|
|
|
|
|
|
|
| |||
| Kidneys (g) | 2.94 ± 0.32 | (13) | 3.03 ± 0.26 | (13) | 3.16 ± 0.27 | (13) | 3.27 ± 0.25* | (13) |
| |||
|
| 0.66 ± 0.06 |
| 0.66 ± 0.05 |
| 0.69 ± 0.05 |
| 0.79 ± 0.06** |
|
| |||
|
|
|
|
|
|
|
|
|
|
| |||
| Spleen (g) | 0.77 ± 0.11 | (13) | 0.76 ± 0.07 | (13) | 0.76 ± 0.09 | (13) | 0.73 ± 0.10 | (13) |
| |||
|
| 0.17 ± 0.02 |
| 0.17 ± 0.02 |
| 0.17 ± 0.02 |
| 0.18 ± 0.02 |
|
| |||
Thymus (mg)
|
389.8 ± 122.5 86.8 ± 25.7
|
(13)
|
370.1 ± 55.2 80.8 ± 10.8
|
(13)
|
375.7 ± 67.3 82.5 ± 14.9
|
(13)
|
313.5 ± 97.5 74.3 ± 18.3
|
(13)
| |||||
Testes (g) | 3.04 ± 0.29 | (13) | 3.01 ± 0.21 | (13) | 3.02 ± 0.38 | (13) | 3.14 ± 0.21 | (13) | |||||
| 0.68 ± 0.06 |
| 0.66 ± 0.07 |
| 0.66 ± 0.07 |
| 0.76 ± 0.09* |
| |||||
Epididymides (g) |
1.10 ± 0.12 |
(13) |
1.04 ± 0.10 |
(13) |
1.07 ± 0.13 |
(13) |
1.06 ± 0.10 |
(13) | |||||
| 0.24 ± 0.03 |
| 0.23 ± 0.03 |
| 0.23 ± 0.03 |
| 0.26 ± 0.04 |
| |||||
Final body weight (g) | 302.5 ± 14.1 | (10) | 308.1 ± 29.3 | (6) | 301.5 ± 20.3 | (13) | 284.9 ± 34.6 | (8) | |||||
Liver (g) |
12.87 ± 1.01 |
(10) |
13.16 ± 1.49 | (6) |
14.15 ± 2.26 |
(13) |
14.59 ± 3.05 | (8) | |||||
| 4.26 ± 0.38 |
| 4.27 ± 0.29 |
| 4.70 ± 0.67 |
| 5.10 ± 0.68* |
| |||||
Kidneys (g) |
2.09 ± 0.24 |
(10) |
2.00 ± 0.28 | (6) |
2.14 ± 0.24 |
(13) |
2.09 ± 0.11 | (8) | |||||
Female | 0.69 ± 0.08 |
| 0.65 ± 0.07 |
| 0.71 ± 0.07 |
| 0.74 ± 0.06 |
| |||||
Spleen (g) |
0.66 ± 0.09 |
(10) |
0.60 ± 0.10 | (6) |
0.56 ± 0.07 |
(13) |
0.57 ± 0.11 | (8) | |||||
| 0.22 ± 0.03
|
| 0.19 ± 0.01
|
| 0.19 ± 0.02
|
| 0.20 ± 0.03
|
| |||||
Thymus (mg) | 190.5 ± 49.5 | (10) | 168.7 ± 39.2 | (6) | 177.5 ± 76.6 | (13) | 154.7 ± 68.4 | (8) | |||||
| 62.8 ± 15.0 |
| 55.1 ± 13.4 |
| 58.5 ± 24.5 |
| 52.6 ± 19.5 |
| |||||
Values are expressed as Mean ± S.D.
Parenthesis indicates number of animals
a: absolute weight
b: relative weight (g or mg per 100 g body weight)
*: significant difference from control, p<0.05
**: significant difference from control, p<0.01
Table 8: Histopathological findings of rats treated with TBBS in the combined repeat dose and reproductive/developmental toxicity screening test
| Organ findings, grade and number of animals | Sex | male | female | ||||||
| Dose (mg/kg bw/d) | 0 | 40 | 200 | 1000 | 0 | 40 | 200 | 1000 | |
| Kidney | |||||||||
| Number of animals evaluated | 13 | 13 | 13 | 13 | 13 | 13 | 13 | 13 | |
| Eosinophilic body | total | 6 | 13** | 13** | 13** | 0 | 0 | 0 | 0 |
| +/- | 2 | 5 | 6 | 1 | |||||
| + | 1 | 7 | 5 | 2 | |||||
| ++ | 3 | 1 | 1 | 10 | |||||
| +++ | 0 | 0 | 1 | 0 | |||||
Basophilic tubule cortex | total | 9 | 9 | 7 | 8 | 4 | 3 | 6 | 1 |
| ± | 7 | 9 | 5 | 8 | 3 | 3 | 6 | 1 | |
| + | 2 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | |
| ++ | 0 | 0 | 1 | 0 | |||||
Degeneration, vacuolar, proximal tubule | total | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 3 |
| ± | 0 | 0 | 3 | 1 | |||||
| + | 0 | 0 | 0 | 2 | |||||
**significant difference from control, p<0.01 (Mann-Whitney U test)
Table 9: Summary of reproductive performance in parental rats treated orally with TBBS in the combined repeat dose and reproductive/development toxicity screening test
| Dose (mg/kg) |
| ||
0 | 40 | 200 | 1000 | |
Number of mated pairs | 13 | 13 | 13 | 13 |
Number of copulated pairs | 12 | 12 | 13 | 13 |
Copulation index A | 92.3 | 92.3 | 100 | 100 |
Number of pregnant animals | 10 | 7 | 13 | 9 |
Fertility index B | 83.3 | 58.3 | 100 | 69.2 |
Pairing days until copulation Mean ± S.D. | 3.2 ±2.1 | 2.3 ± 1.1 | 3.7 ± 1.7 | 3.0 ± 2.8 |
Frequency of vaginal estrus Mean ± S.D. | 1.1 ± 0.3 | 1.0 ± 0.0 | 1.2 ± 0.4 | 1.0 ± 0.0 |
Copulation index = (Number of copulated pairs/Number of mated pairs) X 100: % Fertility index = (Number of pregnant animals/Number of copulated pairs) X 100: % |
| |||
Table 10: Summary of development of pups from dams treated orally with TBBS in the combined repeat dose and reproductive/developmental toxicity screening test
| Dose (mg/kg) |
| ||
0 | 40 | 200 | 1000 | |
Number of pregnant females | 10 | 7 | 13 | 9 |
Number of pregnant females with pups alive | 10 | 6 | 13 | 8 |
Gestation index A | 100 | 85.7 | 100 | 88.9 |
Gestation length in days | 22.3±0.5 (10) | 22.5±0.5 (6) | 22.4±0.5 (13) | 22.5±0.5 (8) |
Number of corpora lutea | 16.5±2.0 (10) | 15.9±2.3 (7) | 17.2±2.2 (13) | 15.7±2.6 (9) |
Number of implantation sites | 14.0±4.0 (10) | 14.0±5.5 (7) | 14.5±5.3 (13) | 12.8±5.8 (9) |
Implantation index B | 84.3±19.6 (10) | 85.7±31.1 (7) | 83.0±26.6 (13) | 78.5±30.2 (9) |
Day 0 of lactation |
|
|
|
|
Number of pups born | 13.0±4.1 (10) | 13.3±6.0 (7) | 13.8±5.2 (13) | 11.0±5.8 (9) |
Delivery index C | 92.7±9.0 (10) | 83.0±36.7 (7) | 94.9±5.6 (13) | 75.8±31.5 (9) |
Number of pups alive | 12.9±4.0 (10) | 13.1±5.9 (7) | 13.5±4.9 (13) | 10.9±5.8 (9) |
Birth index D | 92.1±8.6 (10) | 82.2±36.4 (7) | 93.2±4.8 (13) | 75.1±31.8 (9) |
Live birth index E | 99.4±1.9 (10) | 99.1±2.3 (6) | 98.3±2.7 (13) | 98.9±3.2 (8) |
Pup weight in grams |
|
|
|
|
Male | 6.8±0.9 (10) | 6.5±0.3 (6) | 6.7±1.0 (13) | 6.5±0.9 (8) |
Female | 6.5±1.0 (10) | 6.2±0.4 (5) | 6.5±0.9 (13) | 6.2±0.7 (8) |
Sex ratio F | 52.7±14.7 (10) | 49.2±9.3 (6) | 48.9±7.8 (13) | 44.3±10.1 (8) |
Day 4 of lactation |
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Number of pups alive | 12.7±4.1 (10) | 13.0±5.9 (7) | 13.3±4.8 (13) | 10.6±5.5 (9) |
Viability index G | 97.8±5.4 (10) | 98.8±2.9 (6) | 99.1±2.2 (13) | 97.8±6.2 (8) |
Pup weight in grams |
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Male | 11.0±1.8 (10) | 9.6±0.8 (6) | 10.3±2.6 (13) | 9.9±2.0 (8) |
Female | 10.5±1.8 (10) | 9.5±0.7 (6) | 9.8±2.3 (13) | 9.5±1.6 (8) |
Values are expressed as Mean ± S.D. Parenthesis indicates the number of litters evaluated Gestation index = (Number of pregnant females with pups alive/Number of pregnant females) X 100: % Implantation index = ( Number of implantation sites/Number of corpora lutea) X 100: % Delivery index = (Number of pups born/Number of implantation sites) X 100: % Birth index = (Number of pups alive on day 0/Nmber of implantation sites) X 100: % Live birth index = (Number of pups alive on day 0/Number of pups born) X 100: % Sex ratio = (Number of male pups alive on day 0/Number of pups alive on day 0) X 100: % Viability index = (Number of male pups alive on day 4/Number of male pups alive on day 0) X 100: % |
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Applicant's summary and conclusion
- Conclusions:
- NOEL(fertility): 200 mg/kg.
NOAEL(fertility) at least 1000 mg/kg bw/day
NOAEL(developmental): at least 1000 mg/kg bw/day - Executive summary:
Study design
In a combined oral repeat dose reproductive/developmental toxicity screening test [OECD TG 422] rats were dosed by gavage at 40, 200 and 1000 mg/kg bw/day for 42 days in males and from 14 days before pregnancy to day 3 of lactation in females.
Results
N-tert-butyl-2-benzothiazolesulfenamide at the dose levels aplied did not exert adverse effects on copulation and ovulation. Fertility indices in the 40 and 1000 mg/kg groups were lower than the control level. However the low index observed in the 40 mg/kg group seemed to be an artificial finding because all the females in the 200 mg/kg group were found to be fertile. No relation between the low index observed in the 1000 mg/kg group and the adminisatrion of N-tert-butyl-2-benzothiazolesulfenamide was found. Thus, the no effect level for fertility was 200 mg/kg.
No dose related abnormalities were observed with regard to parturition and lactation. There were no adverse effects on viability, the sex ratio and body weights of pups in any N-tert-butyl-2-benzothiazolesulfenamide treated group.
N-tert-butyl-2-benzothiazolesulfenamide at the dose levels applied did not demonstrate teratogenicity.
Conclusion
The no observed adverse effect level (NOAEL) of N-tert-butyl-2-benzothiazolesulfenamide for reproductive and developmental toxicity was 1000 mg/kg/day in males and females.
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