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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1982
Report date:
1982
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
when compared to the 1981 guideline: no opthalmological examination, no coagulation parameters and blood electrolytes
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
2-methylpropane-2-thiol (CAS # 75-66-1)
IUPAC Name:
2-methylpropane-2-thiol (CAS # 75-66-1)
Details on test material:
TS: t-butyl mercaptan (2-methylpropane-2-thiol)
Source: NGO Corporation, Baytown, Texas
Lot No. : ODB
Purity: > 99.0%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age at study initiation: not reported
- Weight at study initiation: 205-215 g for males, 161-164g for females
- Housing: individually (animals were maintained within the exposure chambers)
- Diet (e.g. ad libitum): Purina® Certified Pelleted Rodent Chow® #5002
- Water (e.g. ad libitum): tap water
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72-84
- Humidity (%): 32-68
- Air changes (per hr): animals were maintained within the exposure chambers
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
clean air
Details on inhalation exposure:
Animal Exposure Methods:
Exposures were conducted in 1 m3 glass and stainless steel exposure chambers. Air for chamber ventilation was supplied by an HVAC system separate from the general laboratory systems. This air was particulate filtered and controlled for temperature and humidity. Chamber airflow varied (between 130 and 300 liters/minute) depending on desired exposure concentrations. Exposure temperature and humidity were recorded each day after 3 and 6 hours of exposure, except on the one day each week when the exposure was shortened to 4.5 hours for animal observations. On these days the temperature and humidity were recorded at 3 and 4.5 hours (see Table A, below).

Exposure Atmosphere Generation Methods:
Vapor atmospheres of 2-methylpropane-2-thiol were generated utilizing a counter-current vaporization system. Due to the large range of liquid flow rates required, two types of fluid metering devices were used: a FMI pump and two Sage Syringe Drives.
The system operates as follows: a FMI pump or a Sage Syringe Drive delivers the test material at a known constant rate to the top of the glass bead column. Air is passed up the bead column in a counter-current manner relative to the liquid. Vaporization occurs within the bead column. The concentrated vapors are piped to the exposure chamber air inlet where dilution with chamber ventilation air reduces the concentration to the desired level. Prior to the initiation of each day's exposure, the generation system was brought up to its operational conditions. Table B (see below) summarizes the operational characteristics of the various generation systems used for 2-methylpropane-2-thiol.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Actual exposure concentrations were measured by non-dispersive IR utilizing Wilks MIRANT 1-A analyzers. These analyzers were calibrated by volumetric dilution of the test material in a closed-loop calibration system as recommended by the instrument's manufacturer. The calibration of the IR analyzer was checked prior to each day's exposure. Utilizing an automated sampling system, exposure concentrations in each chamber were monitored at approximately hourly intervals.
Table C (see below) summarizes the exposure concentration data by presenting the mean of the 13 weekly mean nominal and actual exposure concentrations.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6-hours per day, 5-days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
10, 100 and 200 ppm
Basis:
other: target concentration
Remarks:
Doses / Concentrations:
9, 97 and 196 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
15
Control animals:
yes, sham-exposed
Details on study design:
Post-exposure period: None

Examinations

Observations and examinations performed and frequency:
GENERAL OBSERVATIONS
1. Appearance and Behavior
All animals were observed in detail individually for pharmacotoxic signs once each week.

2. Mortality
Twice each exposure day, prior to exposure and again after exposure, all animals were observed for mortality and overt toxicity. On non-exposure days observations were conducted once in the morning and once in the afternoon.

3. Body Weights
Body weights for all animals were recorded once each week on the day that detailed observations for pharmacotoxic signs were made. On the day that body weights and detailed observations were made exposures were shortened to approximately 4.5 hours.

CLINICAL LABORATORY TESTS
Whenever possible, hematological and serum biochemical evaluations were performed on the same 5-male and 5-female rats from each group prior to exposure and after approximately 6 and 12 weeks of exposure.
Blood was obtained via puncture of the orbital sinus plexus from rats fasted overnight (approximately 16 hours).
1. Hematology
Hematological determinations included: hemoglobin, hematocrit, erythrocyte countl, total leucocyte count, platelet count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), differential leucocyte count and sulfhemoglobin.
2. Biochemistry
Biochemical determinations included: blood urea nitrogen (BUN), alkaline phosphatase, total bilirubin, aspartate aminotransferase (formerly SGOT), alanine aminotransferase (formerly SGPT), total protein, albumin, A/G ratio (calculated), glucose and whole blood cholinesterase.

Sacrifice and pathology:
SACRIFICE AND MACROSCOPIC EXAMINATIONS
After approximately 13 weeks of inhalation exposure to the test material, all surviving rats were sacrificed by intraperitoneal sodium pentobarbital administration followed by exsanguination from the abdominal aorta. These and ail rats which died spontaneously or were sacrificed in extremis were subjected to complete postmortem examinations under the direct supervision of a pathologist.
The postmortem examination consisted of an evaluation for external abnormalities including palpable masses and an inspection of orifices. The skin was then reflected from a ventral midline incision taking care not to enter the thoracic cavity. The trachea was exposed and clamped, the thoracic cavity opened and the lungs removed and examined while inflated. The heart was then removed and weighed. The lungs and trachea were deflated and weighed then reinflated via the trachea with 10% neutral buffered formalin. The abdominal cavity was examined for abnormalities and the organs removed, weighed when appropriate and placed in fixative. The urinary bladder was inflated through the wall with the fixative and left unopened for examination after fixation. The skull was opened, the brain examined and removed and the eyes removed. The pituitary was examined in situ and removed with surrounding sella turcica. The muscle was stripped off the vertebral column and spinal cord fixed intact after cutting into the vertebral column in at least two separate sites.

ORGAN WEIGHTS
The following organs from all terminally sacrificed animals were trimmed free of fat and connective tissue and weighed:
heart, kidneys, lung and trachea, testes or ovaries (after fixation), liver, brain, spleen, adrenal (after fixation)

HISTOPATHOLOGY
Microscopic examination of fixed hematoxylin-eosin stained paraffin sections was performed for all animals from the control and high level groups (also at low and mid dose for lungs and kidneys) , including those dying during the course of the study, sacrificed in extremis or from the terminal sacrifice. The following tissues were examined by an IRDC staff pathologist:
adrenals (both), aorta, brain (3 sections), cecum, colon, esophagus, eye and optic nerve, gonade, heart, kidney (both), liver, lungs (all 5 lobes), tumors
lymph nodes (bronchial, cervical, mesenteric) and any other tissue(s) with lesions, nasal turbinate, pancreas, pituitary, prostate/uterus, salivary gland (submaxillary), skin, small intestine (jejunum), spleen, sternum (bone marrow), stomach, trachea, thyroid/parathyroid (if present, in section), urinary bladder.
Statistics:
Generally, when the number of animals in any one group was equal-toor-less-than seven, non-parametric analyses were conducted utilizing the Kruskal-Wallis one-way analysis of variance followed, where appropriate, with the Mann-Whitney U. In those cases where the number of animals in all groups was greater than seven and the measurements were at least on an interval scale (continuous data) parametric analyses were conducted utilizing Bartlett's Chi-square test for homogeneity of variance, followed where appropriate, by an analysis of variance and then where appropriate by Dunnett's -t. In all cases the level of rejection was at the five percent level.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
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:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
In general, the exposed animals displayed no pharmacotoxic signs that were considered to be exposure-related. Alopecia and some instances of ocular discharge were observed.
Only one animal died during the course of the study, a male in Group VI. The death may have been related to blood collection trauma, as it died shortly after blood collection for the 6-week interval.

BODY WEIGHT (Tables 1 and 2)
There were no statistically significant exposure-related effects on body weight in males or females. It appears that there could be some dose-response effect on body weight in males, but this observation vas not as apparent in female rats. Therefore, these apparent dose-response trends are not considered to be of toxicological importance.

HAEMATOLOGY (Tables 3 and 4)
After approximately 6 weeks of exposure, the erythrocyte count was slightly decreased (-7%) in female rats of Group VI when compared to the female control group. The values obtained are not considered to be outside a "normal" range and are not considered to be of biological significance.
After approximately 12 weeks of exposure, the erythrocyte count was slightly decreased in female rats of Groups VI (-5%) and VII (-4%) when compared to the female control group . The erythrocyte count for females falls within the range of historical normal values, with the control group being toward the high end of that range. Thus, the apparent dose-response reduction in erythrocyte count of females may be a random occurrence and of no toxicological significance.

CLINICAL CHEMISTRY (Tables 5 and 6)
After approximately 6 weeks of exposure, the only parameter for which a statistically significant difference was observed was for the slightly elevated BUN (+34%) of Group VI males. Due to the fact that this was a singular occurrence and that the value is still within the "normal" range, this difference is probably not biologically important.
After approximately 12 weeks of exposure, there were no statistically significant differences observed in any of the exposure groups with respect to any of the parameters when judged against the control group.

ORGAN WEIGHTS (Table 7)
Absolute and relative kidney weights were statistically significantly elevated in males of Groups VI (+24% and +19%) and VII (+23% and +28%). These observed differences may also be exposure-related, as the differences are observed in the two highest exposure groups for t-butyl mercaptan. Again, no such effect was observed in the females exposed to the same test material. Various other statistically significant differences observed with respect to organ weights are not considered to be biologically meaningful.

GROSS PATHOLOGY
No compound-related macroscopic lesions were observed in any of the rats that were sacrificed at the termination of the study or those that died during the course of the study.

HISTOPATHOLOGY: NON-NEOPLASTIC
Test article-related microscopic changes were observed in lungs of male and female rats and in the kidneys of the male rats.
There was a compound related increase in alveolar macrophages among males and females of the mid dose (97 ppm) and high dose (196 ppm) groups exposed to t-butyl mercaptan. At the mid dose level, 5 of 15 males and 3 of 15 females were affected. All lesions were trace in severity. At the high dose level 14 of 15 males and 12 of 15 females were affected. One male and one female were mild and all of the others were trace in severity. This lesion did not occur at the low dose level (9 ppm) and it was considered to be the no effect level.
Evaluation of the kidneys of male rats exposed to t-butyl wercaptan at 196 ppm showed trace to moderate chronic nephrosis in 14 of the 15 animals. The lesion consisted of varying degrees of multifocal degeneration of the proximal convoluted tubules, tubular regeneration and inflammatory cell infiltration of the interstitium. This lesion, nephrosis and/or regeneration occurred in the mid and low dose groups males, 7 of 15 at the low dose level and 13 of 15 at the mid dose level. It was considered to be compound related at all three dose levels.
Incidental non-treatment-related lesions were observed in adrenal, heart, liver, branchial and cervical lymph nodes, nasal turbinates, prostate, testes, trachea, eye, stomach and thymus.

Effect levels

Key result
Dose descriptor:
NOAEC
Remarks:
systemic toxicity
Effect level:
>= 196 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 196 ppm = 721 mg/m3

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1 : male animals, mean body weight (g)

Week

Mean bw (sd)

Group I (control)

Group V (10 ppm)

Group VI (100 ppm)

Group VII (200 ppm)

ALLOC

205(7.2)

210(8.3)

215(8.5)

210 (9.5)

1

278(15.7)

289(17.4)

296(16.5)

270(25.4)

2

312(16.8)

325(21.1)

330(21.8)

308(20.9)

3

342(19.2)

359(26.4

360(24.5)

338(24.6

4

370(21.4)

383(31.2)

382(31.5)

359(28.2)

5

380(23.0)

399(30.1)

385(53.8)

376(36.7)

6

398(24.5)

415(33.4)

400(46.7)

392(37.5)

7

410(24.8)

427(37.9)

431(44.1)

402(39.0)

8

432(31.7)

448(40.3)

450(50.0)

421(38.0)

9

451(31.9)

468(42.6)

468(48.2)

442(41.4)

10

457(34.4)

473(46.4)

470(47.6)

448(44.1)

11

460(36.6)

482(47.9)

477(50.1)

452(42.4)

12

463(36.7)

479(48.8)

476(54.4)

442(55.9)

13

463(41.8)

481(51.3)

486(57.0)

449(62.0)

Table 2 : female animals, mean body weight (g)

Week

Mean bw (sd)

Group I (control)

Group V (10 ppm)

Group VI (100 ppm)

Group VII (200 ppm)

ALLOC

162(6.0)

161(6.4)

163(5.9)

164(4.4)

1

194(11.4)

193(13.1)

194(9.2)

195(10.2)

2

209(12.0)

209(14.0)

207(9.8)

212(12.5)

3

216 (13.7)

220(13.8)

218(11.9)

222(11.7)

4

229(15.3)

227(17.3)

228(10.3)

230(13.7)

5

233(17.5)

253(17.0)

233(12.7)

233(20.3)

6

239(18.5)

237(18.5)

236(14.7)

241(18.1)

7

244(20.2)

242(20.5)

241(14.2)

247(19.5)

8

249(21.6)

251(22.5)

248(13.8)

256(20.5)

9

256(22.2)

257(23.4)

257(14.2)

263(19.9)

10

258(21.6)

252(21.0)

255(25.6)

267(19.8)

11

263(22.7)

259(21.5)

254(18.7)

270(20.8)

12

262(25.7)

255(21.3)

254(21.8)

266(23.4)

13

267(24.5)

267(28.4)

254(30.2)

271(22.8)

Table 3: Mean(sd) hematological vales, week 6

Group

Sex

Leucocytes 103/cm3

RBC 106/cm3

Hb g/dl

Ht %

MCV µ3

MCH g

MCHC g/dl

Platelets 103/cm3

Neutro-philes seg/100WBC

Lympho-cytes /100WBC

SulHb g/dl

I

M

12.7(3.14)

8.10(0.462)

17.6(1.20)

47.1(3.02)

58(1.5)

21.8(0.38)

37.4(0.40)

647(53.9)

22(10.7)

74(9.7)

0(0)

V

M

11.7(3.01)

8.18(0.371)

18.1(0.71)

47.2(2.05)

58(0.8)

22.1(0.50)

38.2(0.60)

637(60.2)

21(11.1)

73(11.0)

0(0)

VI

M

20.8(19.8)

6.92(1.94)

15.3(4.10)

40.2(10.5)

58(1.8)

22.1(0.55)

31.9(0.51)

677(98.6)

18(6.2)

75(7.7)

0(0)

VII

M

14.6(3.55)

7.61(0.82)

16.7(0.96)

43.6(2.85)

57(3.0)

22.1(1.49)

38.4(0.54)

590(64.9)

23(5.5)

74(6.5)

0(0)

I

F

10.0(2.55)

7.66(0.23)

17.1(0.69)

45.2(2.05)

59(1.3)

22.4(0.46)

37.9(0.36)

629(50.7)

14(6.4)

83(6.1)

0(0)

V

F

8.2(2.93)

7.58(0.33)

16.7(0.49)

44.1(2.14)

59(1.2)

22.1(0.36)

37.5(0.90)

604(89.9)

17(10.9)

78(11.5)

0(0

VI

F

10.0(2.87)

7.18*(0.32)

16.4(1.21)

43.3(3.47)

60(2.6)

22.7(0.74)

37.8(0.72)

623(44.1)

19(6.6)

78(5.1)

0(0)

VII

F

9.7(1.62)

7.54(0.354)

16.8(0.62)

44.1(1.50)

59(1.0)

22.3(0.32)

38.1(0.46)

635(144.2)

19(3.7)

77(2.6)

0(0)

WBC -White blood cells Leucocytes

*Statistically different from the control group mean, p<0.05

Table 4: Mean(sd) hematological vales, week 12

Group

Sex

Leucocytes 103/cm3

RBC 106/cm3

Hb g/dl

Ht %

MCV µ3

MCH g

MCHC g/dl

Platelets 103/cm3

Neutro-philes seg/100WBC

Lympho-cytes /100WBC

SulHb g/dl

I

M

11.1(3.65)

8.37(0.217)

17.7(0.66)

50.1(2.50)

60(3.2)

21.1(0.26)

35.0(2.05)

766(51.9)

21(14.0)

77(15.0)

0(0)

V

M

10.2(1.31)

8.67(0.329)

18.1(0.75)

50.5(1.74)

58(2.6)

20.8(0.44)

35.8(0.90)

737(93.2)

19(3.6)

78(3.1)

0(0)

VI

M

9.8(2.60)

8.11(0.547)

17.6(0.86)

48.6(1.87)

58(2.1)

21.2(0.50)

36.3(1.23)

754(33.8)

20(7.4)

77(6.2)

0(0)

VII

M

12.5(3.66)

7.71(1.469)

16.1(2.91)

47.0(8.40)

61(7.1)

21.2(0.92)

34.8(2.48)

925(289.6)

21(12.6)

76(12.0)

0(0)

I

F

9.4(3.10)

7.91(0.130)

17.6(0.60)

49.8(3.23)

63(4.7)

22.2(0.76)

35.3(2.38)

762(140.0)

13(3.8)

83(4.1)

0(0)

V

F

7.2(2.66)

7.99(0.248)

17.8(0.75)

49.6(3.02)

62(2.1)

22.3(0.81)

36.1(1.43)

714(151.2)

14(1.8)

84(2.6)

0(0)

VI

F

9.4(2.89)

7.55*(0.203)

17.1(0.57)

46.8(1.02)

62(0.7)

22.6(0.35)

36.5(0.51)

762(81.0)

20(11.5)

74(10.0)

0(0)

VII

F

7.1(0.63)

7.63*(0.187)

17,1(0.86)

46.9(2.69)

62(2.1)

22.5(0.78)

36.5(0.75)

770(87.6)

14(2.7)

84(3.0)

0(0)

WBC - Whitebloodcells

* Significantly different from control group mean, p<0.05

** Significantly different from control group mean, p<0.01

Table 5: Mean (sd) biochemical Values, 6 Weeks

Group

Sex

BUN (mg/dl)

Alk. Phosp. (IU/L)

Total bilirubin (mg/dl)

AST (IU/l)

ALT (UI/l)

Total protein (g/dl)

Albunin (g/dl)

A/G ratio

Glucose (mg/dl)

Cholines-terase (µM/ml/min)

I

M

11.9(1.38)

97(14.8)

0.1(0.05)

92(26.6)

40(5.4)

7.2(0.34)

3.5(0.14)

1.0(0.05)

96(13.8)

4.2(0.39)

V

M

13.2(2.90)

85(20.7)

0.2(0.05)

90(16.5)

35(4.7)

6.8(0.26)

3.3(0.17)

1.0(0.05)

97(15.9)

4.3(0.25)

VI

M

16.0*(1.79)

75(16.4)

0.2(0.08)

100(42.2)

43(8.6)

6.9(0.89)

3.3(0.40)

0.9(0.04)

92(12.1)

3.8(0.91)

VII

M

14.3(1.66)

80(17.4)

0.2(0.05)

96(44.1)

38(4.5)

6.9(0.36)

3.4(0.12)

0.9(0.05)

92(10.3)

4.1(0.34)

I

F

15.2(1.04)

49(12.1)

0.2(0.05)

76(6.6)

32(4.8)

7.7(0.42)

3.8(0.29)

1.0(0.08)

97(9.4)

5.5(0.70)

V

F

14.6(1.88)

57(11.6)

0.2(0.08)

91(32.0)

33(8.8)

7.3(0.24)

3.7(0.19)

1.0(0.10)

101(14.0)

5.3(0.42)

VI

F

14.2(0.62)

52(11.5)

0.2(0.00)

101(36.1)

59(63.0)

7.5(0.36)

3.8(0.24)

1.0(0.05)

94(13.4)

5.7(0.71)

VII

F

16.0()2.76

59()15.0

0.2()0.05

93(6.8)

36(3.8)

7.7(0.49)

3.8(0.27)

1.0(0.08)

88(10.4)

5.4(0.62)

*Significanrly different from control group mean, p<0.05

Table 6: Mean (sd) biochemical Values, 12 Weeks

Group

Sex

BUN (mg/dl)

Alk. Phosp. (IU/L)

Total bilirubin (mg/dl)

AST (IU/l)

ALT (UI/l)

Total protein (g/dl)

Albunin (g/dl)

A/G ratio

Glucose (mg/dl)

Cholines-terase (µM/ml/min)

I

M

12.4(1.83)

71(15.8)

0.2(0.04)

89(19.2)

34((6.1)

7.1(0.42)

3.5(0.09)

1.0(0.10)

97(10.7)

4.1(0.17)

V

M

12.9(2.65)

63(13.6)

0.2(0.04)

99(23.0)

33(6.1)

7.1(0.29)

3.5(0.11)

1.0(0.07)

90(11.1)

4.4(0.22)

VI

M

14.9(1.17)

66(24.3)

0.2(0.04)

94(19.9)

36(7.5)

7.4(0.60)

3.6(0.30)

1.0(0.15)

90(13.3)

4.3(0.34)

VII

M

13.4(1.18)

59(11.0)

0.1(0.05)

106(20.3)

32(6.7)

6.7(0.38)

3.3(0.29)

1.0(0.08)

88(8.3)

4.2(0.41)

I

F

12.6(1.80)

39(11.9)

0.2(0.04)

80(3.5)

30(6.2)

7.6(0.58)

4.0(0.33)

1.1(0.08)

91(18.1)

5.3(0.76)

V

F

12.6(3.30)

46(4.5)

0.2(0.04)

80(10.3)

29(1.8)

7.7(0.63)

4.0(0.28)

1.1(0.08)

110(22.2)

5.7(0.70)

VI

F

15.2(3.09)

43(12.5)

0.2(0.04)

89(11.3)

25(2.6)

7.5(0.33)

3.9(0.19)

1.1(0.05)

85(16.1)

5.2(0.74)

VII

F

12.1(1.08)

41(16.5)

0.2(0.00)

89(10.4)

28(3.5)

7.5(0.47)

3.9(0.23)

1.1(0.07)

96(17.0)

5.5(0.48)

Applicant's summary and conclusion

Conclusions:
2-methylpropane-2-thiol induced an increase of kidney weights in male rats exposed to 97 and 196 ppm and a chronic nephropathy in all males. It has been shown in the OECD 422 study that 2-methylpropane-2-thiol induced male rat-specific hyaline droplets nephropathy with no relevance for human risk assessment (Hard et al., 2009). The NOAEC for systemic toxicity is higher or equal to 196 ppm.

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.
Takahashi K, Lindamood C and Maronpot RP (1993) Retrospective Study of Possible alpha-2µ-Globulin Nephropathy and Associated Cell Proliferation in Male Fischer 344 Rats Dosed with t-Butyl Alcohol. ENVIRON-HEALTH-PERSPECT, 101(SUPPL 5), 281-286.
Executive summary:

In a 13-week inhalation toxicity study, male and female Sprague-Dawley rats (15/sex/dose) were exposed (whole body) to 2 -methylpropane-2-thiol at measured concentrations 0, 9, 97, or 196 ppm (0, 33, 357 or 721 mg/m3, respectively) for six hours per day, five days per week. 

There were no deaths, clinical signs of toxicity or body weight changes observed. Blood urea nitrogen was statistically significantly different from the control group at the 6-week interval only for the 97 ppm exposure group; this change was not considered biologically relevant because it occurred at only one time interval. Statistically significant differences in erythrocyte count were only found in females at 6-week (97 ppm) and 12-week (97 and 196 ppm). The clinical pathology endpoints that differed from concurrent controls remained within the range of historical control values and were not considered to be biologically or toxicologically relevant. No compound-related macroscopic lesions were observed in any of the rats that were sacrificed at the termination of the study or those that died during the course of the study. There was a compound related increase in alveolar macrophages among males and females of the mid dose (97 ppm) and high dose (196 ppm) groups exposed to t-butyl mercaptan. At the mid dose level, 5 of 15 males and 3 of 15 females were affected. All lesions were trace in severity. At the high dose level 14 of 15 males and 12 of 15 females were affected. One male and one female were mild and all of the others were trace in severity. This lesion did not occur at the low dose level (9 ppm). Toxicologically significant increases in the mean weights of kidneys occurred in male rats exposed to 97 and 196 ppm. There was a compound and concentration-related increase in chronic nephrosis (varying degrees of multifocal degeneration of the proximal convoluted tubules, tubular regeneration, and inflammatory cell infiltration of the interstitium) in 14 of 15 animals at the high concentration (196 ppm). The lesion was also noted in 13 of 15 at the mid concentration (97 ppm) and 7 of 15 animals at the low concentration (9 ppm). However, findings in the kidneys of males were considered to be rat-specific with no relevance for human risk assessment.

The NOAEC for systemic toxicity was determined to be ≥ 196 ppm (721 mg/m3).

This study received a Klimisch score of 2 and is classified as reliable with restriction.