Dodecane-1-thiol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test

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; 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)

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

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.

Details on mating procedure:

No data reported

Duration of treatment / exposure:

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

Frequency of treatment:

Once daily

Duration of test:

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

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Sperm parameters (Parental animals)
No data

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.

Fetal examinations:

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 (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: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
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 (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: other:

2

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: other:

3

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no treatment-related effects at any dose on offspring.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: embryotoxic / teratogenic effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental 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:

Octane-1-thiol (a structural analogue of dodecane-1-thiol in the category) has been tested in a reproduction/developmental toxicity screening (TG 422) study (MHLW, 2004; Klimisch score = 1). 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 36thday for the males and on the 5thday post-partum/after birth for the females and pups respectively. There was 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 the offspring.

The NOAELs for maternal and developmental toxicity for this study are 10 and 250 mg/kg/day.

This study received a Klimisch score of 1 because although a study report was not available for this study and some data were not reported in study summaries, OECD determined that this study was reliable without restrictions.