Dodecane-1-thiol

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

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

Adequacy of study:

key study

Study period:

Not available

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)

GLP compliance:

yes

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; octane-1-thiol (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:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMAL
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 status was 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 grams
Female; 202-254 grams

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

No data reported

Details on mating procedure:

No data reported

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Test solutions were analyzed and warranted to be stable for 9 days. No other data on analytical verification was reported.

Duration of treatment / exposure:

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

Frequency of treatment:

Once daily

Details on study schedule:

Terminal killing (parental animals):
Male; day 36,
Female; day 5 of lactation
Offspring; 4 days after birth

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 10, 50, 250 mg/kg/day
Basis:
no data

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Examinations

Sperm parameters (parental animals):

No data

Litter observations:

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, physical or behavioural abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals on day 36
- Maternal animals: All surviving animals on day 5 post-partum

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [3, 4, 5, and 6] were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals were sacrificed at 5 days of age.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera

HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [3, 4, 5, and 6] were prepared for microscopic examination and weighed, respectively.

Statistics:

Five percent (significant level)
Multiple comparison test, multiple comparison test of Kruskal-Wallis and Dunnett type, and Fisher's exact test were performed.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

effects observed, treatment-related

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

effects observed, treatment-related

Details on results (P0)

Maternal toxicity (Mortality and toxicological changes of dams):

No deaths were observed. Some toxicological changes were observed at forestomach in 50 and 250 mg/kg/day groups. And severe changes were observed at many organs in the 250 mg/kg/day group.

Reproductive and developmental toxicity

(1) Reproductive performance

-At 250 mg/kg/day group: Extension of mean estrous cycle was observed.
-At 10 and 50 mg/kg/day group: No abnormality was observed.

(2) Delivery and lactation
-At 250 mg/kg/day group: Extension of gestation length and low value of delivery index were observed.
-At 10 and 50 mg/kg/day group: No abnormality was observed.

(3) Morphology, body weight and necropsy findings of offspring

There were no toxicological significances related with test substance in any treatment group.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

Reproductive/Developmental Toxicity

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

reproductive performance

2

Dose descriptor:

NOAEL

Remarks:

Reproductive/Developmental Toxicity

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Extension of mean estrous cycle and gestation length and low value of delivery index were observed for females in 250 mg/kg/day group.

3

Dose descriptor:

NOAEL

Remarks:

Maternal Toxicity

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Some toxicological changes were observed at forestomach in 50 and 250 mg/kg/day groups. And severe changes were observed at many organs in the 250 mg/kg/day group.

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Details on results (F1)

There were no treatment-related effects at any dose on offspring. 

Effect levels (F1)

Dose descriptor:

NOAEL

Remarks:

Offspring

Generation:

F1

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Table 1. Reproductive performance

Dose (mg/kg/day)	0	10	50	250
No. of animals	12	12	12	12
Mean estrous cycle	3.98	4.00	4.08	4.36**
No. of females with irregular estrous cycle	0/12	0/12	0/12	0/12
Mating period/  No. of estrous	0.0	0.0	0.0	0.1
Day of conceiving	1.7	2.3	2.0	2.6
Copulation index (%) ^a	91.7	100.0	100.0	100.0
Fertility index (%) ^b	100.0	100.0	91.7	100.0

^a: (No. of copulated females)/(No. of pairs)
^b: (No. of pregnant females)/(No. of copulated females)
*: Significant difference from control, p<0.05
** Significant difference from control, p<0.01

Table 2. Delivery data

Dose (mg/kg/day)	0	10	50	250
n	11	12	11	12
Gestation length (days)	22.2	22.7	22.5	22.8**
No. of corpora lutea	16.8	16.2	16.6	17.3
No. of implantation sites	15.9	14.9	15.9	16.3
Total No. of offspring	15.7	14.5	15.3	13.9
Implantation index (%)	94.23	91.62	95.43	93.93
Delivery index (%)	98.85	97.41	95.97	85.85**
Gestation index (%) a)	100.0	100.0	100.0	100.0

^a: (No. of pregnant animals delivered live offspring)/(No.of pregnant animals)
*: 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

 

Table 5. 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

 

Table 6. 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 reproduction/developmental toxicity study where groups of male and female rats exposed to octane-1-thiol, study results indicated the NOAEL for reproductive/developmental toxicity was 250 and 50 mg/kg bw/day for males and females respectively; the NOAEL for maternal toxicity was 10 mg/kg bw/day; and the NOAEL for the offspring was 250 mg/kg bw/day.

Executive summary:

In a reproduction/developmental study (OECD 422), groups of male and female Sprague-Dawley rats (Crj: CD(SD) IGS, SPF; 12/sex/dose) were administered 0, 10, 50 or 250 mg/kg bw/day of octane-1-thiol (CAS Number 111-88-6) by gavage in olive oil daily for 35 days in males and from 14 days before mating to day 4 of lactation for females. The animals were sacrificed on the 36^th day for the males and on the 5^th day post-partum/after birth for the females and pups respectively.

No treatment-related mortality occurred during the study. There were no treatment-related effects at any dose on reproductive and developmental parameters for males. For females, there was an extension of the mean estrous cycle and gestation length as well as a low delivery index at 250 mg/kg bw/day. Necropsy revealed significant maternal toxicity effects to the stomach, spleen, and thymus in females at 50 and 250 mg/kg bw/day. Females also 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. There were no treatment-related effects at any dose on offspring. 

The NOAEL for reproductive/developmental toxicity was 250 and 50 mg/kg bw/day for males and females respectively. The NOAEL for maternal toxicity was 10 mg/kg bw/day. The NOAEL for the offspring was 250 mg/kg bw/day.  

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