Propane-2-thiol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study was classified as reliable without restriction because it follow sound scientific guidelines.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Reference 2

Reference Type:

publication

Title:

Inhalation teratology studies of n-butyl mercaptan in rats and mice

Author:

Thomas WC, Seckar JA, Johnson JT, Ulrich CE, Klonne DR, Schardein JL, Kirwin CJ

Year:

1987

Bibliographic source:

Fundamental and Applied Toxicology 8: 170-178

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

concentrations were administered by inhalation instead of orally; limited information on animal husbandry and methods

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Butane-1-thiol

EC Number:

203-705-3

EC Name:

Butane-1-thiol

Cas Number:

109-79-5

Molecular formula:

C4H10S

IUPAC Name:

butane-1-thiol

Test material form:

liquid: volatile

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

- Source: The Charles River Breeding Laboratories Inc., Portage, Michigan, USA
- Age at study initiation: approximately 14 weeks old
- Weight at study initiation: 221-303 grams at the time of mating
- Housing: individually housed, except during mating, in suspended wire-mesh cages
- Diet (e.g. ad libitum): Purina® Certified Rodent Chow #5002
- Water (e.g. ad libitum): tap water
- Acclimation period: 26 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

Animal Exposure Methods:
Exposures were conducted in one cubic meter glass and stainless steel exposure chambers. Air for the chamber ventilation was supplied from a HVAC system separate from the general laboratory systems. This air was particulate filtered (99.9% + 0.3 µ) and controlled for temperature and humidity. Chamber airflow rate varied between 200 and 260 L/min depending on desired exposure concentrations.
Exposure chamber temperatures and relative humidities were recorded each day alter three and six hours of exposure. Table 1 presents the minimum and maximum and the mean temperature and relative humidity at the six hour measurement time for each group over the course of the study.

Exposure Atmosphere Generation Methods:
A vapor atmosphere of the test material was generated utilizing a counter-current vaporization system. This system operated as follows: The test material was pumped at a known and constant rate to the top of the bead column by a FMI® fluid metering pump or Sagee syringe drive. Dry-compressed air passed up the bead column in a countercurrent manner relative to the liquïd.Vaporization occurred on the bead column. The concentrated vapors were piped to the exposure chamber air inlet where dilution with chamber ventilation air reduced the concentration to the desired level. Table 2 summarizes the vapor generation system operating conditions.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Nominal exposure concentrations were calculated for all exposures. Actual exposure concentrations were measured by non-dispersive Infrared spectrophotometry utilizing a Wilks (MIRAN®) lA analyzer. The analyzer was calibrated by volumetric dilution of pure (99%) n-Butyl Mercaptan in saran gas bags. The calibration was checked once daily

Details on mating procedure:

One female and one male animal of the same species and strain were placed together for mating. The occurrence of copulation was determined by daily inspection for a copulatory plug. The day evidence of mating was detected was designated day 0 of gestation and the female was returned to an individual cage.

Duration of treatment / exposure:

6 hrs/day

Frequency of treatment:

Gestation days 6 through 19

Duration of test:

until GD20

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 ppm

Remarks:

36.9 mg/m³ air (analytical) (group 2)

Doses / concentrations 2

Dose / conc.:

75 ppm

Remarks:

250.9 mg/m³ air (analytical) (group 3)

Doses / concentrations 3

Dose / conc.:

150 ppm

Remarks:

560.7 mg/m³ air (analytical)

No. of animals per sex per dose:

25

Control animals:

yes, sham-exposed

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
Prior to initiation of the treatment period all animals were observed twice daily for mortality and overt changes in appearance and behavior. All animals were observed daily for mortality and clinical signs of toxicity from gestation day 6 through sacrifice.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
Individual maternal body weights were recorded on gestation days 0, 6, 9, 12, 16 and 20.

FOOD CONSUMPTION: No

WATER CONSUMPTION : No

POST-MORTEM EXAMINATIONS: Yes
On gestation day 20, all surviving dams were sacrificed by carbon dioxide inhalation. The abdominal and thoracic cavities and organs of the dams were examined for grossly evident morphological changes and the carcasses discarded. Uteri from females that appeared nongravid were placed in 10% ammonium sulfide solution for confirmation of pregnancy.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes
All fetuses were individually weighed and examined for external malformations and variations, including the palate and eyes. Each fetus was externally sexed and individually numbered and tagged for identification.

- Soft tissue examinations: Yes
Approximately one-half of the fetuses were placed in Bouin's fixative for subsequent visceral examination by razor-blade sectioning as described by Wilson.

- Skeletal examinations: Yes
The remaining one-half of the fetuses were fixed in alcohol, macerated in potassium hydroxide and stained with Alizarin Red S by a method similar to that described by Dawson2 for subsequent skeletal examination.

- Head examinations: No

Statistics:

The male to female fetal sex distribution and the numbers of fetuses and litters with malformations were compared using the X2 test criterion with Yate's correction for 2X2 contingency tables and/or Fisher's exact probability test. The numbers of early and late resorptions, nonviable fetuses, and postimplantation loss were compared by the Mann-Whitney U test. The mean numbers of viable fetuses, total implantations, and corpora lutea, and mean fetal body weights were compared by analysis of variance (one way classification). Bartlett's test for homogeneity of variances, and the appropriate t test using Dunnett's multiple comparison tables were used to judge significance of differences. All statistical analyses compared the treatment group to the control group with the level of significance at p<0.05.

Historical control data:

Available in the report.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Description (incidence and severity):

A slight increase in the incidence of hair loss on the limbs was noted in group 4 when compared to the control group (group 1). Female #76523 and 76554 in groups 3 and 4 respectively, were dehydrated, Twenty-one rats had soft stool; 10, 8, 2 and 1 in the control, low (group 2), mid (group 3) and high (group 4) dose groups, respectively.

Mortality:

no mortality observed

Description (incidence):

Survival was 100% in all groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A very slight reduction in mean maternal body weight gain from gestation days 6-20 and over the entire gestation period (gestation days 0-20) was noted in the rats in the n-butyl Mercaptan treated groups 3 and 4 when compared to the control group. Similarly, the adjusted (dam weight on gestation day 20 minus gravid uterus weight) mean materna! body weight gain from gestation days 0-20 was reduced in these groups when compared to the control group. The mean maternal body weight gain during these intervals in group 2 was comparable to the control group. The adjusted mean materna! body weight gain from gestation days 0-20 was slightly reduced in this group when compared to the control group.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Both the mean absolute and relative kidney weights in the treated groupa were comparable to the control group.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

In female #76548 in group 4 the spleen was mottled, pitted and adhered to the connective tissue.In female #76547 in group 4 the left kidney was pitted.

Description (incidence and severity):

In female #76548 in group 4, moderate focal capsular fibrosis was noted in spleen at histopathological examination.

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

There were no biologically meaningful or statistically significant differences in the mean number of viable fetuses, postimplantation loss, total implantations, corpora lutea, or the fetal sex distribution in the treated groups when compared to the control group and the historical control data.

Effect levels (maternal animals)

Dose descriptor:

NOAEC

Effect level:

>= 560.7 mg/m³ air (analytical)

Remarks on result:

not determinable due to absence of adverse toxic effects

Maternal abnormalities

Abnormalities:

effects observed, non-treatment-related

Results (fetuses)

Fetal body weight changes:

no effects observed

Description (incidence and severity):

A statistically significant (p<0.05) increase in mean fetal body weight was present in group 3. This increase was within the range of the historical control data and was considered due to random occurrence.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Single instances of tail anomaly with associated small or no anal opening, scoliosis and/or pelvic anomaly were noted in one litter each in the groupa 3 and 4. The incidence of these malformations in the fetuses of groups 3 and 4 was within the range of occurrence in the historical control data and was not considered biologically meaningful.
There were no biologically meaningful trends in the occurrence of developmental and genetic variations in fetuses (or litters) in the treated groups when compared to the control group.

Effect levels (fetuses)

Dose descriptor:

NOAEC

Effect level:

>= 560.7 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

No teratogenic effects occurred in rats when n-butyl Mercaptan was administered by whole body inhalation at the 560 mg/m3 actual exposure level.

Executive summary:

Pregnant female rats (COBS CD; 25/group) were exposed (inhalation, whole body) to n-butyl mercaptan at target concentrations of 0, 10, 75 and 150 ppm (0, 36.9, 250.9 and 560.7 mg/m3 analytical, respectively) for 6 hours/day during gestation days (GD) 6-19. The study design was similar to EPA Test Guideline OPPTS 870.3700 and OECD TG 414. All rats survived until study termination. During the in-life portion of the study, a very slight decrease in mean maternal body weight gain was noted in the two highest exposure groups (75 and 150 ppm), and females from the highest exposure group (150 ppm) showed a slight increase (2/25 females) in the incidence of hair loss around the limbs as compared to control females. There was a statistically significant increase in mean fetal body weights in the group exposed at 75 ppm; however, because the increase was within the range of the historical control data, the finding was not considered to be treatment-related. Of the noted fetal malformations, all were within the range of occurrence in the historical control data and not considered to be biologically significant. In conclusion, there were no developmental/teratogenic effects or maternal toxicity in rats when administeredn-butyl mercaptanby whole body inhalation at or below the 150 ppm, the NOAEC for both maternal and fetal toxicity was 150 ppm (560.7 mg/m3 analytical).