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EC number: 200-861-4 | CAS number: 75-33-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- 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:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- The histopathological examination of the reproductive organs was only performed on 5 animals/sex of the control and top dose.
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 272.2-325.1 g for males, 188.1-235-9 g for females
- Housing:no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum):no data
- Acclimation period:no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-27
- Humidity (%): 35-75
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-12 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- no details available
- Duration of treatment / exposure:
- Exposure period: Males: 42 days; Females: 42-53 days from 14 days before mating to day 4 of lactation
Premating exposure period (males): 2 weeks
Premating exposure period (females): 2 weeks
Duration of test: 10, 50, 200 mg/kg bw/day - Frequency of treatment:
- Once daily
- Remarks:
- Doses / Concentrations:
10, 50, 200 mg/kg bw/day
Basis: - No. of animals per sex per dose:
- Males: 12
Females: 17 for control and top dose, 12 for low and mid doses - Control animals:
- yes, concurrent vehicle
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
General condition was observed 2 or 3 times a day throughout the administration period
DETAILED CLINICAL OBSERVATIONS: Yes
Detailed clinical observation was carried out once a week in all animals throughout the administration period. In pregnant females, it was carried out on days 7, 14, and 20 of gestation and on day 4 of lactation. Sensory reaction test, grip strength, and motor activity were examined at 6 weeks of administration in males and on day 4 of lactation in pregnant females.
BODY WEIGHT: Yes
Body weights were measured on days 1 (before dosing), 4, 8, 11, 15, 18, 22, 25, 30, 32, 36, 39, and 42 of administration for males, For females, body weight was measured on days 1 (before dosing), 4, 8, 11, 15, 18, 22, 25, 30, 32, 36, 39, and 42 of administration, except for pregnant females for whom it was measured on days 0, 7, 14, and 20 of gestation and days 0 and 4 of lactation. Further, it was measured at necropsy in both sexes.
FOOD CONSUMPTION :
Food consumption was measured on days 1 (before dosing), 4, 8, 11, 15, 30, 32, 36, 39, and 42 of administration for males. For females, food consumption was measured on days 1 (before dosing), 4, 8, 11, 15, 30, 32, 36, 39, and 42 of administration, except for pregnant females for whom it was measured on days 1, 7, 14, and 20 of gestation and days 1 and 4 of lactation
WATER CONSUMPTION : No - Oestrous cyclicity (parental animals):
- yes
- Sperm parameters (parental animals):
- No
- Litter observations:
- STANDARDISATION OF LITTERS
Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
Necropsy was carried out at the day following the end of the administration and recovery periods
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
- The testis and epididymis of all males were weighed.
HISTOPATHOLOGY / ORGAN WEIGHTS
The testis, epididymis, prostate, and seminal vesicles of 5 males at 0 and 200 mg/kg bw/day were microscopically examined at the end of the administration period. Further, the ovary, uterus, and vagina of 5 females at 0 and 200 mg/kg bw/day were microscopically examined at the end of the administration period. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed at 5 days of age.
- These animals were subjected to postmortem macroscopic examination for gross abnormalities. - Statistics:
- Statistical methods: X2 test was used for mating index, males and females fertility indices, gestation index, and delivery index were used. Wilcoxon Rank Sum Test Method for implantation index, death birth index, live birth index, and viability index on day 4 were used.
- Reproductive indices:
- Estrous cycle, number of copulated, number of pregnant females, mating length, mating index (# of pairs with successful copulation/# of pairs mating × 100), males or females fertility indices (# of pregnant animals/#of animals with successful mating×100), number of females with live pups, gestational length, number of corpora lutea, number of implantations, number of pups delivered, number of live pups delivered, gestation index (# of females with live pups/# of pregnant females × 100), implantation index (# of implants/# of corpora lutea × 100), delivery index (# of pups born/# of implants × 100), death birth index (number of stillborns/number of litter × 100), were determined.
- Offspring viability indices:
- Sex ratio, live birth index (# of live pups born/# of pups born × 100), and viability index on day 4 (# of live pups on postnatal day (PND) 4 /# of live pups born × 100) were determined.
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Remarks:
- parental toxicity
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: decreased body weight gain at 200 mg/kg/day
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive performance and developmental toxicity
- Effect level:
- >= 200 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: no effect
- Clinical signs:
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not specified
- Histopathological findings:
- not examined
- Dose descriptor:
- NOAEL
- Remarks:
- neonatal toxicity
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: Decreased pup body weights
- Reproductive effects observed:
- not specified
- Conclusions:
- The test substance had no effects on any reproductive or developmental parameter. The NOAEL for reproductive and developmental toxicity was considered to be >= 200 mg/kg bw/day and the NOAEL for parental and neonatal toxicity is considered to be 50 mg/kg/day.
- Executive summary:
The OECD Test Guideline 422 study conducted for t-butyl mercaptan is described in Section 3.1.5. In this study, groups of male and female Sprague-Dawley rats (12-17/sex/dose) were administered 0, 10, 50 or 200 mg/kg bw/day of t-butyl mercaptan by gavage in corn oil daily for 42-53 days. The animals were dosed daily for 2 weeks prior to mating, during mating and gestation, and the females were dosed for 4 days post-partum after which the adult females and their pups were terminated. There were no treatment-related effects at any dose on reproductive and developmental parameters including mating index, fertility index, duration of gestation, gestation index, total number of pups born, live birth index, number of pups alive and viability index on day 4 of lactation or sex ratio. Decreases in body weight of live pups on PND 4 were observed in both sexes at 200 mg/kg bw/day. All reproductive organs from adult animals were normal grossly and microscopically. The NOAEL for reproductive performance and developmental toxicity was 200 mg/kg bw/day and the NOAEL for parental and neonatal toxicity was considered to be 50 mg/kg bw/day.
A low body weight value was observed in both sexes at 200 mg/kg bw/day throughout the administration period. During the recovery period, a lower body weight was observed in females, but their body weight gains throughout the recovery period were similar to those of the control group.
A low food consumption value or a tendency toward a low value was observed in males at 200 mg/kg bw/day on days 4 and 15 of administration and in females at 200 mg/kg bw/day throughout the administration period. During the recovery period, females exhibited lower food consumption on day 1 of the recovery period, but food consumption after day 4 of the recovery period was similar to the control group. A decrease in food consumption was observed in females at 10mg/kg on day 15 of the administration period. However, it was not observed at 50mg/kg and not considered to be a dose-related effect.
ORGAN WEIGHTS (PARENTAL ANIMALS)
There were increases in relative weights of the testes and epididymides in males at 200 mg/kg. However, absolute weights of these organs were not changed, and no histopathological changes were observed in these organs. These changes were considered to be due to decreases in body weights.
Increases in absolute and relative weights of the epididymides were observed at 50mg/kg, but these changes were not considered to be dose related effects because these effects were not observed at 200 mg/kg bw/day.
Decreases in body weight of live pups on PND 4 were observed in both sexes at 200 mg/kg bw/day.
Reproductive performance of rats
Dose (mg/kg bw/day) |
0 |
10 |
50 |
200 |
Number of females eximaned |
12 |
12 |
12 |
12 |
Count of estrus |
3.67(0.78) |
3.92(0.29) |
3.83(0.58) |
3.83(0.39) |
Estrus cycle |
3.97(0.10) |
4.00(0.00) |
4.03(0.10) |
4.00(0.00) |
No. of pairs mating |
12 |
12 |
12 |
12 |
No. of pairs with successful mating |
12 |
12 |
12 |
12 |
No. of pregnant females |
12 |
12 |
12 |
11 |
Duration of mating |
2.75(1.42) |
3.33(2.84) |
3.58(3.18) |
3.36(1.80) |
Fertility index (%) |
100 |
100 |
100 |
91.67 |
Terminal delivery of F0 dams
Dose (mg/kg bw/day) |
0 |
10 |
50 |
200 |
No. of females with live pups |
12 |
12 |
12 |
11 |
Gestational length (day) |
22.08(0.29) |
22.50(0.52) |
22.33(0.65) |
22.18(0.40) |
# of corpora lutea |
15.08(2.11) |
14.58(2.61) |
15.67(2.15) |
15.36(1.96) |
# of implantation sites |
14.25(1.76) |
13.42(3.00) |
14.92(2.75) |
14.45(3.00) |
# of pups delivered |
13.75(1.82) |
13.08(3.34) |
14.08(3.20) |
13.64(2.77) |
Sex ratio (male/female) |
0.83 |
1.20 |
0.92 |
0.88 |
# of live pups on day 4 |
13.75(1.82) |
13.00(3.28) |
13.75(3.11) |
13.64(2.77) |
Viability index on day 4 |
98.79 |
98.08 |
96.97 |
99.33 |
Body weight of live newborns (g) |
||||
Male Day 0 |
6.4(0.5) |
6.9(0.6) |
6.7(0.7) |
6.2(0.2) |
Male Day 4 |
10.3(0.8) |
10.3(2.2) |
10.0(2.4) |
8.6(0.9)** |
Female Day 0 |
6.1(0.6) |
6.4(0.6) |
6.3(0.6) |
5.9(0.2) |
Female Day 4 |
9.8(0.9) |
9.8(2.0) |
9.5(2.4) |
8.2(0.9)** |
Number with external anomalies |
0 |
0 |
0 |
1 |
**:
P<0.01
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
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)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2-methylpropane-2-thiol
- EC Number:
- 200-890-2
- EC Name:
- 2-methylpropane-2-thiol
- Cas Number:
- 75-66-1
- Molecular formula:
- C4H10S
- IUPAC Name:
- 2-methylpropane-2-thiol
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 272.2-325.1 g for males, 188.1-235-9 g for females
- Housing:no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum):no data
- Acclimation period:no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-27
- Humidity (%): 35-75
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- no details available
- Duration of treatment / exposure:
- 42-53 days
- Frequency of treatment:
- Once daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
10, 50, 200 mg/kg bw/day
Basis:
- No. of animals per sex per dose:
- 12 males and 17 females per group at 0 and 200 mg/kg bw/day and 12 males and 12 females per group at 10 and 50 mg/kg bw/day; 12 males and 12 females per group were used for mating. To investigate reversibility, a recovery period of 14 days was established for 5 males and 5 non-mated females at 0 and 200 mg/kg bw/day
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: 14 days
- Positive control:
- not relevant
Examinations
- Observations and examinations performed and frequency:
- Clinical observations and frequency:
General condition was observed 2 or 3 times a day throughout the administration period and once a day throughout the recovery period.
Body weight:
Body weight was measured on days 1 (before dosing), 4, 8, 11, 15, 18, 22, 25, 30, 32, 36, 39, and 42 of the administration period in males. In females, body weight was measured on days 1 (before dosing), 4, 8, 11, 15, 18, 22, 25, 30, 32, 36, 39, and 42 of the administration period. Body weight of pregnant females was measured on days 0, 7, 14, and 20 of gestation and days 0 and 4 of lactation. Body weight was measured at necropsy in both sexes.
Food consumption:
Food consumption was measured on days 1 (before dosing), 4, 8, 11, 15, 30, 32, 36, 39, and 42 of the administration period in males. In females, food consumption was measured on days 1 (before dosing), 4, 8, 11, 15, 30, 32, 36, 39, and 42 of the administration period, and on days 18, 22, and 25 in non-mated females. Food consumption of pregnant females was measured on days 1, 7, 14, and 20 of gestation and days 1 and 4 of lactation.
During the recovery period, body weight and food consumption were measured on days 1, 4, 8, 11, and 14 in both sexes.
Urinalysis:
Urinalysis was carried out for 5 males per group at 6 weeks of the administration period.
Functional observation battery:
Detailed clinical observation was carried out once a week in all animals throughout the administration period. In pregnant females, it was carried out on days 7, 14, and 20 of gestation and on day 4 of lactation. Sensory reaction test, grip strength, and motor activity were examined at 6 weeks of administration in males and on day 4 of lactation in pregnant females.
Hematology and blood biochemistry:
At necropsy, hematology and blood biochemistry were examined in 5 males and 5 females per group. - Sacrifice and pathology:
- Necropsy was carried out at the day following the end of the administration and recovery periods.
Organ weights:
Organs were examined at necropsy. The brain, heart, liver, kidney, adrenal, thymus, thyroids, and spleen of 5 males and 5 females per group and the testis and epididymis of all males were weighed.
Microscopic examination:
The spleen, liver, and kidney in 5 males and 5 females of each group were microscopically examined at the end of the administration and recovery periods. The cerebrum, cerebellum, medulla oblongata, pituitary, thymus, thyroid, parathyroid, adrenal, heart, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, trachea, lung, urinary bladder, spinal cord, mesenteric lymph node, submaxillary lymph node, sciatic nerve, femur (included bone marrow), and sternum (included bone marrow) of 5 males and 5 females at 0 and 200 mg/kg bw/day were microscopically examined at the end of the administration period. The testis, epididymis, prostate, and seminal vesicles of 5 males at 0 and 200 mg/kg bw/day were microscopically examined at the end of the administration period. Further, the ovary, uterus, and vagina of 5 females at 0 and 200 mg/kg bw/day were microscopically examined at the end of the administration period. Additionally, kidney tissue was immunohistochemically examined by staining with anti-alpha2u-globulin. - Statistics:
- Statistical methods: For numerical data, Dunnett's test (homogeneous) or Steel test (heterogeneous) was used. Steel Multiple comparison test was used for urinary of test paper method. Wilcoxon's rank sum test was used for detailed clinical observation data, sensory reaction test data. Fisher exact probability test for necropsy data and Mann-Whitney U-test method for histopathology data were used.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There was no death in any group.
No compound-related changes were observed in any animal.
BODY WEIGHT AND WEIGHT GAIN (see attached figure)
A low value was observed in both sexes at 200 mg/kg bw/day throughout the administration period. During the recovery period, a lower body weight was observed in females, but their body weight gains throughout the recovery period were similar to those of the control group.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
A low value or a tendency toward a low value was observed in males at 200 mg/kg bw/day on days 4 and 15 of administration and in females at 200 mg/kg bw/day throughout the administration period. During the recovery period, females exhibited lower food consumption on day 1 of the recovery period, but food consumption after day 4 of the recovery period was similar to the control group. A decrease in food consumption was observed in females at 10mg/kg on day 15 of the administration period. However, it was not observed at 50mg/kg and not considered to be a dose-related effect.
HAEMATOLOGY
Males:
Administration period (Table 1): Decreases in erythrocyte count, hemoglobin, hematocrit, and MCHC, an increase in platelet count, and prolonged PT and APTT were observed at 200 mg/kg bw/day. A decrease in MCHC was observed at 50 mg/kg bw/day. A decrease in reticulocyte at 10 mg/kg was not considered to be a dose related effect because it was not observed at 50 mg/kg bw/day and higher.
Recovery period (Table 2): Decreases in hemoglobin and MCHC and an increase in reticulocyte ratio were observed at 200 mg/kg bw/day.
Females:
Administration period Table 3): A decrease in erythrocyte count and an increase in reticulocyte ratio were observed at 200 mg/kg bw/day. An increase in reticulocyte at 50 mg/kg bw/day was not considered to be a dose related effect. A shortening of the APTT was observed at 50 mg/kg bw/day and higher.
Recovery period (Table 4): Increases in MCV and MCH and a decrease in MCHC were observed at 200 mg/kg bw/day. An increase in basophile at 200 mg/kg was not considered to be a dose related effect because it was not observed at the end of administration period.
CLINICAL CHEMISTRY
Males:
Administration period (Table 5): Decreases in alpha1-globulin, glucose and chlorine and increases in alpha2-globulin, albumin, gamma-GTP, total cholesterol, and phospholipids were observed at 200 mg/kg bw/day. Increases in total cholesterol and phospholipids at 50 mg/kg bw/day were observed.
Females:
Administration period (Table 6): Decreases in alpha1-globulin and glucose and increases in total protein, A/G ratio, albumin, total cholesterol, and phospholipids were observed at 200 mg/kg bw/day. An increase in total cholesterol was observed at 50 mg/kg bw/day. A decrease in ALP at 50 mg/kg bw/day was not considered to be a dose related effect because it was not observed at 100 mg/kg bw/day.
Recovery period: A decrease in creatinine was observed at 200mg/kg bw/day. However it was not considered to be a dose related effect because this effect was not observed at the end of administration period.
URINALYSIS
No test substance-related changes were observed.
NEUROBEHAVIOUR
No compound-related changes were observed in any animal in the functional observation battery.
ORGAN WEIGHTS
Administration period (Tables 7 and 8): Increases in absolute and relative weights of the liver were observed in males at 50 mg/kg bw/day and above and in females at 200 mg/kg bw/day. In the kidney of males, absolute weight at 50 mg/kg bw/day and above, and relative weight at 10 mg/kg bw/day and above were significantly increased. A decrease in absolute thymus weight was observed in males at 200 mg/kg bw/day. There were increases in relative weights of the heart, thyroids, testes and epididymides in males at 200 mg/kg and of the heart in females at 200mg/kg. However, absolute weights of these organs were not changed, and no histopathological changes were observed in these organs. These changes were considered to be due to decreases in body weights. Increases in absolute and relative weights of the epididymides in males and of the thymus in females were observed at 50mg/kg, but these changes were not considered to be dose related effects because these effects were not observed at 200 mg/kg bw/day.
Recovery period (Tables 9 and 10): Increase in relative liver weight was observed in both sexes at 200 mg/kg bw/day. Furthermore, increases in absolute and relative weights of the kidneys were observed in males at 200 mg/kg bw/day. There were increases in absolute weight of the adrenal in males at 200mg/kg and relative weight of the kidney in females at 200 mg/kg bw/day. However, these effects were not considered to be dose related effects because these changes were not observed at the end of administration period.
GROSS PATHOLOGY
Administration period: Enlargement and discoloration of the kidneys were observed in 1, 3, and 4 males at 10, 50, and 200 mg/kg bw/day, respectively. Liver enlargement was observed in 2 males at 200 mg/kg bw/day.
Recovery period: Kidney enlargement was observed in 1 male at 200 mg/kg bw/day.
HISTOPATHOLOGY: NON-NEOPLASTIC
Administration period (Tables 11 and 12): Histopathological changes were observed in the liver and spleen of both sexes and in the kidneys of males. The histopathological findings were as follows: slight centrilobular hypertrophy of hepatocytes in the liver in 5 males and 3 females at 50 mg/kg bw/day and slight or moderate hypertrophy in all males and females at 200 mg/kg bw/day, hemosiderin deposits in the red pulp in the spleen of both sexes at 200 mg/kg bw/day, periportal fatty degeneration of hepatocytes in the liver in males at 50 mg/kg bw/day and above, basophilic renal tubules in the kidneys in males at 10 mg/kg bw/day and above and hyaline deposits in proximal tubular epithelial cells in the kidneys in males at 10 mg/kg bw/day and above, which indicates alpha2µ-globulin nephropathy.
Recovery period (Tables 13 and 14): Hemosiderin deposits were observed in the red pulp of the spleen of both sexes, and basophilic renal tubules were observed in the kidneys in males at 200 mg/kg bw/day. Periportal fatty degeneration of hepatocytes in the liver was observed in 1 male and 1 female at 200 mg/kg bw/day (4 males and 0 female at the end of the treatment period). Centrilobular hypertrophy of hepatocytes in the liver is not longuer observed after recovery.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: slight reversible hematological and liver effects
- Dose descriptor:
- LOAEL
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: decreased body weight gain and slight reversible hematological and liver effects
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Haematological parameters in males (end of treatment)
Dose (mg/kg bw/day) |
0 |
10 |
50 |
200 |
Erythrocyte count (10^4/uL) |
815(29) |
820(21) |
768(39) |
743(28)** |
Hemoglobin(g/dL) |
14.9(0.5) |
14.9(0.6) |
14.2(0.3) |
13.7(0.5)** |
Hematocrit (%) |
42.2(1.2) |
42.9(1.6) |
40.9(0.9) |
39.8(1.8)* |
MCHC (g/dL) |
35.3(0.2) |
34.9(0.2) |
34.7(0.5)* |
34.5(0.3)** |
Reticulocyte (%) |
2.3(0.2) |
1.8(0.3)* |
2.2(0.2) |
3.5(0.9) |
Platelet count (10^4/uL) |
95.1(5.9) |
96.1(5.9) |
106.6(9.1) |
121.7(19.2)** |
PT (sec) |
14.1(1.1) |
14.8(1.8) |
16.5(4.2) |
21.9(8.9)* |
APTT (sec) |
26.1(1.9) |
27.9(4.3) |
27.0(3.8) |
38.1(7.5)** |
*p<0.05, ** p<0.01; n=5
Mean (Standard Deviation)
Table 2: Haematological parameters in males (end of recovery)
Dose (mg/kg bw/day) |
0 |
200 |
Hemoglobin (g/dL) |
15.5(0.5) |
14.5(0.6)* |
MCHC (g/dL) |
35.8(0.8) |
34.7(0.6)* |
Reticulocyte (%) |
2.3(0.2) |
2.8(0.3)* |
Note: *, p<0.05; n=5
Mean (Standard Deviation)
Table 3: Haematological parameters in females (end of treatment)
Dose (mg/kg bw/day) |
0 |
10 |
50 |
200 |
Erythrocyte count (10^4/uL) |
656(36) |
634(12) |
640(21) |
607(37)* |
Reticulocyte (%) |
4.4(0.7) |
7.0(1.8)* |
5.7(2.1) |
6.4(0.5)* |
APTT (sec) |
19.6 (1.6) |
17.8(1.0) |
17.1(0.8)* |
16.8(1.4)** |
Table 4: Haematological parameters in females (end of recovery)
Dose (mg/kg bw/day) |
0 |
200 |
MCV (fL) |
52.3(0.9) |
54.8(1.2)** |
MCH (pg) |
18.9(0.4) |
19.5(0.3 )* |
MCHC (g/dL) |
36.2(0.4) |
35.6(0.3)* |
Basophile (%) |
0.1(0.0) |
0.2(0.1)* |
Note: *, p<0.05, **; p<0.01; n=5
Table 5: Blood biochemistry parameters in males (end of treatment)
Dose (mg/kg bw/day) |
0 |
10 |
50 |
200 |
alpha1-globulin (%) |
17.9(2.6) |
17.8(1.6) |
16.8(2.3) |
13.7(1.4)* |
alpha2-globulin (%) |
7.6(0.7) |
8.0(0.4) |
8.2(0.6) |
8.8(0.8)* |
Albumin (g/dL) |
2.92(0.22) |
3.04(0.18)* |
2.93(0.16) |
3.43(0.30)* |
gamma-GTP (IU/L) |
0.3(0.2) |
0.5(0.4) |
0.2(0.3) |
0.8(0.4)* |
Total cholesterol (mg/dL) |
60(10) |
73(17) |
85(8)* |
96(15)** |
Phospholipid (mg/dL) |
106(10) |
126(20) |
141(8)* |
171(26)** |
Glucose (mg/dL) |
124(9) |
117(16) |
111(23) |
79(9)** |
Chlorine (mEq/L) |
108.4(2.3) |
107.6(1.6) |
107.0(1.4) |
105.1(2.1)* |
Note:
*, p<0.05 **; p<0.01; n=5
Mean (Standard Deviation)
Table 6: Blood biochemistry parameters in females (end of treatment)
Dose (mg/kg bw/day) |
0 |
10 |
50 |
200 |
Total protein (g/dL) |
5.2(0.3) |
5.4(0.2) |
5.4(0.5) |
6.2(0.4)** |
A/G Ratio |
1.19(0.07) |
1.12(0.12) |
1.20(0.09) |
1.36(0.11)* |
alpha1-globulin (%) |
18.4(1.2) |
17.6(1.8) |
17.9(0.7) |
15.5(2.1)* |
Albumin (g/dL) |
2.85(0.18) |
2.83(0.21) |
2.92(0.25) |
3.57(0.29)** |
ALP (IU/L) |
241(37) |
223(75) |
132(30)* |
177(90) |
Total cholesterol (mg/dL) |
74(3) |
80(7) |
97(8)* |
120(22)* |
Phospholipid (mg/dL) |
144(8) |
145(10) |
173(19) |
223(32)** |
Glucose (mg/dL) |
121(7) |
112(12) |
107(14) |
93(8)** |
Note: *, p<0.05 **; p<0.01; n = 5
Mean (Standard Deviation)
Applicant's summary and conclusion
- Conclusions:
- t-butyl mercaptan induced an increase of kidney weights in males exposed to 50 and 200mg/kg bw/d and a chronic hyaline droplet nephropathy in all males, a rat-specific effect which is with no relevance for human risk assessment (Hard et al., 2009). Based on the decreased body weight gain in both males and females at 200 mg/kg bw/day, the slight reversible hematological changes and the slight or moderate reversible hepatocellular hypertrophy observed in males at 50 and 200 mg/kg bw/d and in females at 200 mg/kg bw/d, the LOAEL is considered to be 200 mg/kg bw/day and the NOAEL is considered to be 50 mg/kg bw/day.
References:
Hard GC, Johnson KJ and Cohen SM (2009) A comparison of rat chronic progressive nephropathy with human renal disease-implications for human risk assessment. CRIT-REV-TOXICOL, 39, 332-346. - Executive summary:
In a combined repeated-dose/reproductive/developmental toxicity screening study (OECD TG 422), Crl:CD(SD) rats were administered 0, 10, 50 or 200 mg/kg bw/day of t-butyl mercaptan by gavage in corn oil daily for 42-53 days and a satellite group in the control and high dose were monitored without dosing for 2-weeks for recovery. Group sizes were12 males and 17 females at 0 and 200 mg/kg bw/day and 12 males and 12 females at 10 and 50 mg/kg bw/day; 12 males and 12 females per group were used for mating and a recovery period of 14 days was established for 5 males and 5 non-mated females at 0 and 200 mg/kg bw/day.
There was no mortality, clinical signs of toxicity or changes in functional observational battery measurements. Decreased body weight was observed in both sexes at 200 mg/kg bw/day throughout the administration period. During the recovery period, a lower body weight was observed in females, but body weight gains throughout the recovery period were similar to those of the control group. Decreased food consumption was observed in males at 200 mg/kg bw/day on days 4 and 15 of administration and in females at 200 mg/kg bw/day throughout the administration period. During the recovery period, females exhibited lower food consumption on day 1 of the recovery period, but food consumption after day 4 of the recovery period was similar to the control group. There was no effect on urinalysis measurements. For males, decreases in erythrocyte count, hemoglobin, hematocrit, and MCHC, an increase in platelet count, prolonged PT and APTT, decreased a-1-globulin, glucose and chlorine, and increased a-2-globulin, albumin, g-GTP, total cholesterol, and phospholipids were observed at 200 mg/kg bw/day. Slight increases in total cholesterol and phospholipids and a decrease in MCHC were observed at 50 mg/kg bw/day. During the recovery period, decreases in hemoglobin and MCHC and an increase in reticulocyte ratio were observed at 200 mg/kg bw/day. For females, decreased erythrocyte count, increased reticulocyte ratio, decreases in a-1-globulin and glucose and increases in total protein, A/G ratio, albumin, total cholesterol, and phospholipids were observed at 200 mg/kg bw/day. A shortening of the APTT was observed at 50 and 200 mg/kg bw/day, and an increase in total cholesterol was observed at 50 mg/kg bw/day. During the recovery period, increases in MCV and MCH, a decrease in MCHC and a decrease in creatinine were observed at 200 mg/kg bw/day. At necropsy, enlargement and discoloration of the kidneys were observed in 1, 3, and 4 males at 10, 50, and 200 mg/kg bw/day, respectively and liver enlargement was observed in 2 males at 200 mg/kg bw/day; after the recovery period, kidney enlargement was observed in 1 male at 200 mg/kg bw/day. No gross findings were recorded for females. Increases in absolute and relative liver weights were observed in males (50 and 200 mg/kg bw/day) and females (200 mg/kg bw/day). Kidney weight in males at 50 and 200 mg/kg bw/day and relative weight at all doses were significantly increased. A decrease in absolute thymus weight was observed in males at 200 mg/kg bw/day. Following the recovery period, increased relative liver weight was observed in both sexes and increases in absolute and relative weights of the kidneys were observed in males at 200 mg/kg bw/day. Histopathological changes were observed in the liver and spleen of both sexes and in the kidneys of males including: slight and/or moderate hepatocellular centrilobular hypertrophy in males at 50 and 200 mg/kg bw/day and in females at 200 mg/kg bw/day; hemosiderin deposits in the red pulp in the spleen of both sexes at 200 mg/kg bw/day; periportal fatty degeneration of hepatocytes in males at 50 and 200 mg/kg bw/day; basophilic renal tubules and hyaline deposits in proximal tubular epithelial cells in the kidneys in males at all doses which were considered to be indicative of a-2µ-globulin nephropathy (a rat-specific effect which is with no relevance for human risk assessment). Following the recovery period, hemosiderin deposits were observed in the red pulp of the spleen of both sexes, basophilic renal tubules were observed in the kidneys in males, and periportal fatty degeneration of hepatocytes was observed in 1 male and 1 female at 200 mg/kg bw/day. Based on the decreased body weight gain in both males and females at 200 mg/kg bw/day, the slight reversible hematological changes and the slight or moderate reversible hepatocellular hypertrophy observed in males at 50 and 200 mg/kg bw/d and in females at 200 mg/kg bw/d, the LOAEL is considered to be 200 mg/kg bw/day and the NOAEL is considered to be 50 mg/kg bw/day.
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