Dodecane-1-thiol

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: A study report was not available for this study, and some data were not reported in study summaries. However, OECD determined that this study was reliable without restrictions.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

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:

not specified

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Octane-1-thiol (CAS # 111-88-6)

IUPAC Name:

Octane-1-thiol (CAS # 111-88-6)

Details on test material:

Substance; 1-octanethiol (CAS No. 111-88-6)
Manufacturer; Kao Corporation (Japan)
Purity; 99.3 wt%
Impurity; C8 beta-gamma 0.6 area %, C10 0.1 area %
Lot No.; 1815
Test substance was stored at room temperature before use.

Test animals

Species:

rat

Strain:

other: Crj:CD(SD)IGS, SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals:
Seven weeks old Sprague-Dawley (Crj:CD(SD)IGS, SPF) rats obtained from Charles River Japan, Inc. They were put in quarantine for 6 days before use, and their performance statuses were observed. Then they were put in pre-breeding before administration, and the clinical signs and estrous
cycles were checked.
-Age at the start of administration;
9 weeks old
-Weight at the start of administration;
Male; 331-379 g
Female; 202-254 g

-Number of animals/group:
Male; 12
Female; 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on oral exposure:

Data were not reported

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Test solutions were analyzed and warranted to be stable for 9 days.

Duration of treatment / exposure:

Male; 35 days,
Female; from 14 days before mating to day 4 of lactation

Frequency of treatment:

Once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0 (vehicle), 10, 50, 250 mg/kg/day
Basis:

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: Terminal killing:
Male; day 36,
Female; day 5 of lactation

Positive control:

Data were not reported

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Data were not reported

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Not reported

BODY WEIGHT: Yes
- Time schedule for examinations: Not reported

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Data were not reported

FOOD EFFICIENCY: Data were not reported

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Data were not reported

OPHTHALMOSCOPIC EXAMINATION: Data were not reported


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Data were not reported
- Anaesthetic used for blood collection: Data were not reported
- Animals fasted: Data were not reported

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Data were not reported
- Animals fasted:Data were not reported

URINALYSIS: Yes
- Time schedule for collection of urine: Data were not reported
- Metabolism cages used for collection of urine: Data were not reported
- Animals fasted: Data were not reported

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Organ weight

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)

Other examinations:

Data were not reported

Statistics:

Statistical analysis:
Five percent (significant level)
-Multiple comparison test; body weight, body weight gain, food consumption, hematology, blood chemistry, organ weight, a part of urinalysis
-Chi-square test; histological findings, a part of urinalysis

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 specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

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 specified

Details on results:

CLINICAL SIGNS AND MORTALITY
No deaths were observed.
Male
-At 250 mg/kg/day group: Salivation and decrease in locomotor activity were observed.
-At 10 and 50 mg/kg/day group: No abnormality was observed.

Female
-At 250 mg/kg/day group: Salivation, abnormal gait and decrease in locomotor activity were observed.
-At 10 and 50 mg/kg/day group: No abnormality was observed.

BODY WEIGHT AND WEIGHT GAIN
Male
-At 250 mg/kg/day group: The body weight and body weight gain were lower than that of control group in the later period of administration.
-At 10 and 50 mg/kg/day group: The body weight was similar with that of control group.

Female
-At 250 mg/kg/day group: The body weight gain was lower than that of control group.
-At 10 and 50 mg/kg/day group: The body weight was similar with that of control group.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Male
There were no statistical significances in food consumption and water consumption.

Female
-At 250 mg/kg/day group: The food consumption was lower than that of control group.
-At 10 and 50 mg/kg/day group: The food consumption was similar with that of control group.

HAEMATOLOGY
Male
-At 250 mg/kg/day group: Decrease in red blood cell count, hemoglobin concentration and MCHC. Increase in MCV and reticulocyte ratio.
-At 10 and 50 mg/kg/day group: There were no toxicological significances related with test substance.

Female
-At 250 mg/kg/day group: Decrease in red blood cell count and MCHC. Increase in MCV, MCH and reticulocyte ratio.
-At 10 and 50 mg/kg/day group: There were no toxicological significances related with test substance.

CLINICAL CHEMISTRY
Male
-At 250 mg/kg/day group: Decrease in concentration of chloride. Increase in concentration of albumin and calcium, and A/G ratio.
-At 10 and 50 mg/kg/day group: There were no toxicological significances related with test substance.

Female
-At 250 mg/kg/day group: Decrease in ALAT (GPT) and total bilirubin. Increase in concentration of triglyceride.
-At 10 and 50 mg/kg/day group: There were no toxicological significances related with test substance.

URINALYSIS
-At all male treated groups: There were no toxicological significances related with test substance.

ORGAN WEIGHTS
Male
-At 250 mg/kg/day group: Increase in weight at spleen (absolute and relative), liver (relative), kidney (relative), heart (relative) Decrease in weight at thymus (absolute and relative); not statistical significant
-At 50 mg/kg/day group: Increase in weight at liver (relative)
-At 10 mg/kg/day group: There were no toxicological significances related with test substance.

Female
-At 250 mg/kg/day group: Increase in weight at spleen (absolute and relative), liver (absolute and relative), adrenal (absolute and relative), kidney (relative) Decrease in weight at thymus (absolute and relative); not statistically significant
-At 10 and 50 mg/kg/day group: There were no toxicological significances related with test substance.

GROSS PATHOLOGY
See the tables

HISTOPATHOLOGY: NON-NEOPLASTIC
See the tables

Effect levels

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on toxicological effects in the spleen and liver in both sexes at the 250 mg/kg bw/day dose.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Organ Weight

Table 1. Absolute organ weight

Male

Dose (mg/kg/day)	0	10	50	250
No. of animals	12	12	12	12
Terminal body weight (g)	461.8	481.2	470.5	436.3
Thymus (mg)	350.0	431.3	413.1	288.1
Spleen (g)	0.748	0.788	0.786	0.903**

*: Significant difference from control, p<0.05
**: Significant difference from control, p<0.01

 

Table 2. Relative organ weight
-Male

Dose (mg/kg/day)	0	10	50	250
No. of animals	12	12	12	12
Heart	0.298	0.288	0.300	0.323**
Liver	2.498	2.528	2.712*	2.925**
Spleen	0.163	0.163	0.168	0.205**
Kidney	0.678	0.688	0.698	0.746**

*: Significant difference from control, p<0.05
**: Significant difference from control, p<0.01

Table 3. Absolute organ weight
-Female

Dose (mg/kg/day)	0	10	50	250
No. of animals	11	12	11	12
Terminal body weight (g)	298.5	313.0	303.8	287.5
Thymus (mg)	202.4	228.8	212.5	159.5
Liver (g)	10.266	10.925	10.560	11.349*
Spleen (g)	0.603	.0700	0.669	0.902**
Adrenal (mg)	74.35	70.74	74.00	93.01**

*: Significant difference from control, p<0.05
**: Significant difference from control, p<0.01

Table 4. Relative organ weight
-Female

Dose (mg/kg/day)	0	10	50	250
No. of animals	11	12	11	12
Thymus (10E-3)	67.05	72.46	68.68	54.82
Liver (g)	3.436	3.491	3.481	3.945**
Spleen (g)	0.202	0.223	0.221	0.313**
Kidney	0.662	0.638	0.638	0.717**
Adrenal (mg)	24.93	22.64	24.40	32.48**

*: Significant difference from control, p<0.05
**: Significant difference from control, p<0.01

Necropsy Findings

Table 5. Necropsy findings
-Male

Dose (mg/kg/day)	0	10	50	250
No. of animals	12	12	12	12
Spleen Dark reddish	0	0	0	7
Stomach Thickening of wall, forestomach	0	0	0	12

 

Table 6. Necropsy findings
-Female

Dose (mg/kg/day)	0	10	50	250
No. of animals	12	12	12	12
Spleen
Dark reddish	0	0	0	3
Enlargement	0	0	0	2
Stomach Thickening of wall, forestomach	0	0	0	12

 

Histological findings
Table 7. Histological findings
-Male

Dose (mg/kg/day)	0	10	50	250
No. of animals	12	12	12	12
Stomach
Edema, forestomach	0	0	2	10**
Erosion, forestomach	0	0	1	4*
Hyperkeratosis	0	0	1	11**
Hyperkeratosis squamous, forestomach	0	0	1	11**
Inflammatory cell infiltration, forestomach	0	0	1	10**
Ulcer, forestomach	0	0	0	1
Spleen
Congestion	0	0	0	3
Extramedullary hematopoiesis, erythrocytic	1	2	2	10**
Hemosiderin deposition	0	0	0	12**
Bone marrow (femur)
Increase in hematopoietic cell, erythrocytic	0	0	0	5*
Thymus
Atrophy	0	0	0	2
Liver
Hypertrophy, hepatocyte, centrilobular	0	0	0	3

*: Significant difference from control, p<0.05
**: Significant difference from control, p<0.01

Table 8. Histological findings
-Female

Dose (mg/kg/day)	0	10	50	250
No. of animals	12	12	12	12
Stomach
Edema, forestomach	0	0	1	7**
Erosion, forestomach	0	0	0	3
Hyperkeratosis	0	0	1	10**
Hyperkeratosis squamous, forestomach	0	0	1	10**
Inflammatory cell infiltration, forestomach	0	0	1	6**
Ulcer, forestomach	0	0	1	0
Spleen
Congestion	0	0	0	4*
Extramedullary hematopoiesis, erythrocytic	6	7	6	12**
Hemosiderin deposition	2	1	3	12**
Thymus
Atrophy	3	0	3	8*
Liver
Hypertrophy, hepatocyte, centrilobular	0	0	1	3

*: Significant difference from control, p<0.05
**: Significant difference from control, p<0.01

Applicant's summary and conclusion

Conclusions:

In a repeated-dose oral toxicity study, male and female rats exposed to octane-1-thiol indicated a NOAEL of 50 mg/kg/day for both males and females.

Executive summary:

In a repeated-dose oral toxicity study (OECD 422), male and female rats (Crj:CD(SD)IGS, SPF; 12/sex/dose) were administered 0, 10, 50 or 250 mg/kg bw of octane-1-thiol (CAS Number 111 -88 -6) by gavage in corn oil daily for 35 days in the males and from 14 days before mating to day 4 of lactation for the females.  

There was no treatment related mortality, clinical signs, or changes in urinalysis measurements in any dose level for either sex. Males exhibited no treatment related changes in food and water consumption while females showed a lower food consumption rate than the control at the highest dose level. Decreased body weight was observed in both sexes at 250 mg/kg bw in the later period of administration. For males, decreased red blood cell count, hemoglobin concentration, MCHC, and concentration of chloride, and increased MCV, reticulocyte ratio, concentration of albumin and calcium and A/C ratio were observed at 250 mg/kg bw.  No toxicological significances were noted at the lower dose levels. For females, decreased red blood cell count, MCHC, ALAT (GPT) and total billirubin, and increased MCV, MCH, reticulocyte ratio, and concentration of triglyceride were observed at 250 mg/kg bw. No toxicological significances were noted at the lower dose levels. 

A relative weight increase of the liver, kidney, heart, and relative and absolute weight increase in spleen as well as a decrease in relative and absolute weight of the thymus was observed in males at 250 mg/kg bw. A relative increase in liver weight was observed for males at 50 mg/kg bw. Females showed an absolute and relative increase in weight of the spleen, liver, adrenal, a relative weight increase in the kidney, and a decrease in absolute and relative weight in the thymus in 250 mg/kg bw. Necropsy revealed the spleen to be dark reddish and thickening of the forestomach wall in males at the highest dose level. Females exhibited a spleen that was dark reddish and enlarged and thickening of the wall of the forestomach at the highest dose level. No other observations were noted in the three lowest dose levels of either sex.

 

Histopathological changes were observed in the stomach, spleen, liver and thymus of both sexes and in the bone marrow (femur) of males including: edema of the forestomach, hyperkeratosis,  forestomach hyperkeratosis squamous, forestomach inflammatory cell infiltration in males and females at 50 and 250 mg/kg bw/day; erosion of the forestomach in males at 50 and 250 mg/kg bw/day and females at 250 mg/kg bw/day; forestomach ulcers in males at 250 mg/kg bw/day and females at 50 mg/kg bw/day; congestion of the spleen in males and females at 250 mg/kg bw/day; erythrocytic extramedullary hematopoiesis in males and females at all dose levels; hemosiderin deposition in males at 250 mg/kg bw/day and females in all dose levels; atrophy of the thymus in males at 250 mg/kg bw/day and females at 0, 50, and 250 mg/kg bw/day; liver hypertrophy, hepatocyte, centrilobular in males at 250 mg/kg bw/day and females at 50 and 250 mg/kg bw/day; and bone marrow increase in hematopoietic cell, erythrocytic in males at 250 mg/kg bw/day.     

 

The toxicological changes in the forestomach in the 50 and 250 mg/kg bw/day groups were attributed to localized inflammation and did not appear to be systemin nature. Based on the toxicological effects observed in the spleen and liver in both male and female rats dosed at the 250 mg/kg bw/day, the NOAEL was considered to be 50 mg/kg/day .

This study received a Klimisch score of 1 and is classified as reliable without restriction because it followed sound scientific guidelines.