Propane-1-thiol

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

This study was classified as reliable with restriction because although it is a GLP guideline study, a study report in English was not available for data verification. However, this study is peer reviewed and considered sufficient for this endpoint.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

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:

yes

Remarks:

The histopathological examination of the reproductive organs was only performed on 5 animals/sex of the control and top dose.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

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:

Test substance: 2-methyl-2-propanethiol
Purity 99.0-99.9%
Lot No. 200501-001

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 272.2-325.1 g for males, 188.1-235-9 g for females
- Housing:no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum):no data
- Acclimation period:no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-27
- Humidity (%): 35-75
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

no details available

Duration of treatment / exposure:

Exposure period: Males: 42 days; Females: 42-53 days from 14 days before mating to day 4 of lactation
Premating exposure period (males): 2 weeks
Premating exposure period (females): 2 weeks
Duration of test: 10, 50, 200 mg/kg bw/day

Frequency of treatment:

Once daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

200 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Males: 12
Females: 17 for control and top dose, 12 for low and mid doses

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
General condition was observed 2 or 3 times a day throughout the administration period

DETAILED CLINICAL OBSERVATIONS: Yes
Detailed clinical observation was carried out once a week in all animals throughout the administration period. In pregnant females, it was carried out on days 7, 14, and 20 of gestation and on day 4 of lactation. Sensory reaction test, grip strength, and motor activity were examined at 6 weeks of administration in males and on day 4 of lactation in pregnant females.

BODY WEIGHT: Yes
Body weights were measured on days 1 (before dosing), 4, 8, 11, 15, 18, 22, 25, 30, 32, 36, 39, and 42 of administration for males, For females, body weight was measured on days 1 (before dosing), 4, 8, 11, 15, 18, 22, 25, 30, 32, 36, 39, and 42 of administration, except for pregnant females for whom it was measured on days 0, 7, 14, and 20 of gestation and days 0 and 4 of lactation. Further, it was measured at necropsy in both sexes.

FOOD CONSUMPTION :
Food consumption was measured on days 1 (before dosing), 4, 8, 11, 15, 30, 32, 36, 39, and 42 of administration for males. For females, food consumption was measured on days 1 (before dosing), 4, 8, 11, 15, 30, 32, 36, 39, and 42 of administration, except for pregnant females for whom it was measured on days 1, 7, 14, and 20 of gestation and days 1 and 4 of lactation

WATER CONSUMPTION : No

Oestrous cyclicity (parental animals):

yes

Sperm parameters (parental animals):

No

Litter observations:

STANDARDISATION OF LITTERS
Performed on day 4 postpartum: no

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

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.

Postmortem examinations (parental animals):

SACRIFICE
Necropsy was carried out at the day following the end of the administration and recovery periods

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
- The testis and epididymis of all males were weighed.

HISTOPATHOLOGY / ORGAN WEIGHTS
The testis, epididymis, prostate, and seminal vesicles of 5 males at 0 and 200 mg/kg bw/day were microscopically examined at the end of the administration period. Further, the ovary, uterus, and vagina of 5 females at 0 and 200 mg/kg bw/day were microscopically examined at the end of the administration period.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at 5 days of age.
- These animals were subjected to postmortem macroscopic examination for gross abnormalities.

Statistics:

Statistical methods: X2 test was used for mating index, males and females fertility indices, gestation index, and delivery index were used. Wilcoxon Rank Sum Test Method for implantation index, death birth index, live birth index, and viability index on day 4 were used.

Reproductive indices:

Estrous cycle, number of copulated, number of pregnant females, mating length, mating index (# of pairs with successful copulation/# of pairs mating × 100), males or females fertility indices (# of pregnant animals/#of animals with successful mating×100), number of females with live pups, gestational length, number of corpora lutea, number of implantations, number of pups delivered, number of live pups delivered, gestation index (# of females with live pups/# of pregnant females × 100), implantation index (# of implants/# of corpora lutea × 100), delivery index (# of pups born/# of implants × 100), death birth index (number of stillborns/number of litter × 100), were determined.

Offspring viability indices:

Sex ratio, live birth index (# of live pups born/# of pups born × 100), and viability index on day 4 (# of live pups on postnatal day (PND) 4 /# of live pups born × 100) were determined.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
A low body weight value was observed in both sexes at 200 mg/kg bw/day throughout the administration period. During the recovery period, a lower body weight was observed in females, but their body weight gains throughout the recovery period were similar to those of the control group.

A low food consumption value or a tendency toward a low value was observed in males at 200 mg/kg bw/day on days 4 and 15 of administration and in females at 200 mg/kg bw/day throughout the administration period. During the recovery period, females exhibited lower food consumption on day 1 of the recovery period, but food consumption after day 4 of the recovery period was similar to the control group. A decrease in food consumption was observed in females at 10mg/kg on day 15 of the administration period. However, it was not observed at 50mg/kg and not considered to be a dose-related effect.

ORGAN WEIGHTS (PARENTAL ANIMALS)
There were increases in relative weights of the testes and epididymides in males at 200 mg/kg. However, absolute weights of these organs were not changed, and no histopathological changes were observed in these organs. These changes were considered to be due to decreases in body weights.
Increases in absolute and relative weights of the epididymides were observed at 50mg/kg, but these changes were not considered to be dose related effects because these effects were not observed at 200 mg/kg bw/day.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

>= 200 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings:

not examined

Details on results (F1)

BODY WEIGHT (OFFSPRING)
Decreases in body weight of live pups on PND 4 were observed in both sexes at 200 mg/kg bw/day.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

50 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: Decreased pup body weights

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Reproductive performance of rats

Dose (mg/kg bw/day)	0	10	50	200
Number of females eximaned	12	12	12	12
Count of estrus	3.67(0.78)	3.92(0.29)	3.83(0.58)	3.83(0.39)
Estrus cycle	3.97(0.10)	4.00(0.00)	4.03(0.10)	4.00(0.00)
No. of pairs mating	12	12	12	12
No. of pairs with successful mating	12	12	12	12
No. of pregnant females	12	12	12	11
Duration of mating	2.75(1.42)	3.33(2.84)	3.58(3.18)	3.36(1.80)
Fertility index (%)	100	100	100	91.67

Terminal delivery of F0 dams

Dose (mg/kg bw/day)	0	10	50	200
No. of females with live pups	12	12	12	11
Gestational length (day)	22.08(0.29)	22.50(0.52)	22.33(0.65)	22.18(0.40)
# of corpora lutea	15.08(2.11)	14.58(2.61)	15.67(2.15)	15.36(1.96)
# of implantation sites	14.25(1.76)	13.42(3.00)	14.92(2.75)	14.45(3.00)
# of pups delivered	13.75(1.82)	13.08(3.34)	14.08(3.20)	13.64(2.77)
Sex ratio (male/female)	0.83	1.20	0.92	0.88
# of live pups on day 4	13.75(1.82)	13.00(3.28)	13.75(3.11)	13.64(2.77)
Viability index on day 4	98.79	98.08	96.97	99.33
Body weight of live newborns (g)
Male Day 0	6.4(0.5)	6.9(0.6)	6.7(0.7)	6.2(0.2)
Male Day 4	10.3(0.8)	10.3(2.2)	10.0(2.4)	8.6(0.9)**
Female Day 0	6.1(0.6)	6.4(0.6)	6.3(0.6)	5.9(0.2)
Female Day 4	9.8(0.9)	9.8(2.0)	9.5(2.4)	8.2(0.9)**
Number with external anomalies	0	0	0	1 (exencephaly open eyelid protruding tongue)

**: P<0.01

Applicant's summary and conclusion

Conclusions:

The test substance had no effects on any reproductive or developmental parameter. The NOAEL for reproductive and developmental toxicity was considered to be >= 200 mg/kg bw/day and the NOAEL for neonatal toxicity is considered to be 50 mg/kg/day.

Executive summary:

In a combined repeated dose/reproductive/developmental toxicity screening test (OECD 422), groups of male and female Sprague-Dawley rats (12-17/sex/dose) were administered 2 -methylpropane-2 -thiol in corn oil by gavage at 0, 10, 50 or 200 mg/kg bw/day daily for 42-53 days. The animals were dosed daily for 2 weeks prior to mating, during mating and gestation, and the females were dosed for 4 days post-partum after which the adult females and their pups were terminated. 

There were no treatment-related effects at any dose on reproductive and developmental parameters including mating index, fertility index, duration of gestation, gestation index, total number of pups born, live birth index, number of pups alive and viability index on day 4 of lactation or sex ratio. Decreases in body weight of live pups on PND 4 were observed in both sexes at 200 mg/kg bw/day. All reproductive organs from adult animals were normal during gross pathology and microscopic evaluations. The NOAEL for reproductive performance and developmental toxicity was 200 mg/kg bw/day and the NOAEL for neonatal toxicity was considered to be 50 mg/kg bw/day.

This study was classified as reliable with restriction because although it is a GLP guideline study, a study report in English was not available for data verification. However, this study is peer reviewed and considered sufficient for this endpoint.