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Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP compliant (except for minor exception listed below), guideline study, available as unpublished report, no restrictions, fully adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
no lot number available of test material
Qualifier:
according to guideline
Guideline:
other: EPA OPPTS 870.3650
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Reference substance 002
Cas Number:
74-84-0
Molecular formula:
C2H6
Test material form:
gas
Details on test material:
- Name of test material (as cited in study report): ethane
- Supplier: MG Industries, 3 Great Valley Parkway, Malvern, Pennsylvania 19355, USA
- Substance type: Industrial gas
- Physical state: colourless gas
- Analytical purity: 99.0% per supplier
- Lot/batch No.: Not available
- Stability under test conditions: 99.86% before study, 99.88% after study
- Storage condition of test material: Ambient
Specific details on test material used for the study:
- Name of test material (as cited in study report): ethane
- Supplier: MG Industries, 3 Great Valley Parkway, Malvern, Pennsylvania 19355, USA
- Substance type: Industrial gas
- Physical state: colourless gas
- Analytical purity: 99.0% per supplier
- Lot/batch No.: Not available
- Stability under test conditions: 99.86% before study, 99.88% after study
- Storage condition of test material: Ambient

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
According to OECD 422 test guideline
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Species: Albino rats (Outbred) VAF/Plus®, Sprague-Dawley derived (CD®), Crl:CD®(SD)IGS BR
- Source: Charles River Laboratories, Raleigh, North Carolina 27610, USA
- Age at study initiation: Approximately 8 weeks
- Weight at study initiation: Males mean 256 g (range 230-284 G); females mean 197 g (range 167-217 g)
- Fasting period before study: None
- Housing: Individually in stainless steel suspended cages with wire mesh floors and fronts (except for mating period when 1 male and 1 female were housed together)
- Diet: Certified Rodent diet No 5002 (PMI Nutrition International, St Louis, Missouri, USA) ad libitum except during exposure
- Water: Municipal water ad libitum except during exposure
- Acclimation period: Approximately 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 20.7 - 23.2°C
- Humidity: 19.96-74.37%
- Air changes (per hr): Not reported
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 24 November 2003 To: 17 January 2004

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 L glass and stainless steel whole-body exposure chamber
- Method of holding animals in test chamber: housed individually, the placement of animals in the chamber was rotated daily to ensure uniform exposure
- System of generating particulates/aerosols: the test substance was delivered from a single cylinder, through a regulator and two backpressure gauges via a flowmeter into the exposure chambers
- Time to T99: 23 minutes maximum
- Airflow rate: 204 Lpm
- Temperature and humidity in chamber: 20-24°C, 28-59%
- Oxygen level: at least 19%
- Air flow rate: minimum flow rate of 200 L/minute
- Air change rate: final airflow set to provide at least one air change in 5 mins (12 air changes/hour)
- Method of particle size determination: determined weekly using a TSI Aerodynamic Particle Sizer
- Treatment of exhaust air: filtered through a system which consisted of a coarse filter, a HEPA filter and an activated charcoal bed

TEST ATMOSPHERE
- Brief description of analytical method used: Infrared spectrophotometer (IR) 4 times per chamber per day
- Samples taken from breathing zone: yes
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: until evidence of mating was seen, or for two consecutive weeks
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually in plastic "shoebox" cages with bedding
- After the mating period was over, females without evidence of copulation were removed from the mating cages, housed individually and monitored for visible signs of pregnancy with corresponding bodyweight gain.
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Exposure levels were determined using an infrared spectrophotometer 4 times/chamber/day. The test substance was evenly distributed within each chamber. The mean (± SD) analytical concentrations were 0.0 ± 0.0, 1599 ± 59, 5186 ± 285 and 16380 ± 626 ppm.
Duration of treatment / exposure:
Males for 2 weeks prior to mating and for an additional 28 days (minimum) after mating.
Females for 2 weeks prior to mating and gestation days 0-19.
Frequency of treatment:
6 hours/day, 7 days/week
Details on study schedule:
Females without evidence of mating that appeared to be pregnant were killed on an estimated gestation day 19.
Females that littered and their offspring were killed on post partum day 4.
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
Group 1
Analytical Doses / Concentrations:
0.0 ± 0.0 ppm
Dose / conc.:
1 600 ppm
Remarks:
Group 2
Analytical Doses / Concentrations:
1599 ± 59 ppm
Dose / conc.:
5 000 ppm
Remarks:
Group 3
Analytical Doses / Concentrations:
5186 ± 285 ppm
Dose / conc.:
16 000 ppm
Remarks:
Group 4
Analytical Doses / Concentrations:
16380 ± 626 ppm
No. of animals per sex per dose:
12
Control animals:
yes, sham-exposed
Details on study design:
n/a
Positive control:
n/a

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (mortality and clinical condition)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: - Time schedule: Male rats were examined prior to randomisation and once weekly throughout the study. Female rats were examined prior to randomisation and once weekly throughout the premating period and on gestation days 0, 7, 14, 20 and lactation days 0 (except if parturition was not completed on the same day), 1 and 4.

BODY WEIGHT: Yes
- Time schedule for examinations: Male rats were weighed at randomisation and then weekly throughout the study. Females were weighed at randomisation, on the first day of exposure and twice weekly until evidence of copulation was observed, on gestation days 0, 7, 14 and 20, and on lactation days 1 and 4. Females were not fasted prior to recording terminal bodyweights.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Once weekly throughout the premating period. For pregnant or confirmed mated females, food consumption was recorded on gestation days 0-7, 7-14, 14-20 and on lactation days 1-4.

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

Oestrous cyclicity (parental animals):
No
Sperm parameters (parental animals):
During the microscopic examination of the testes, special emphasis was placed on the stages of spermatogenesis and the histopathology of interstitial testicular cell structure.
Litter observations:
Not applicable
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals (after a minimum of 28 days post-mating).
- Maternal animals: All surviving animals (28 days post-mating).

GROSS NECROPSY: Yes (all animals).
- Tissues examined: adrenal glands, bone (sternum/femur), bone marrow, brain (medulla/pons, cerebrum and cerebellum), epididymides, heart, kidneys, caecum, colon, rectum, larynx, liver, lungs (with mainstem bronchi), lymph nodes (mesenteric and mediastinal), mammary glands (with adjacent skin), nasopharynx, ovaries (with oviducts), prostate, seminal vesicles, duodenum, ileum, jejunum, spinal cord (cervical, thoracic and lumbar), spleen, stomach, testes, thymus, thyroid with parathyroids, tibial nerve, trachea, urinary bladder, uterus with vagina and all macroscopic lesions and tissue masses.

ORGAN WEIGHTS: Yes. Adrenal glands, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, testes, thymus and uterus with vagina.

HISTOPATHOLOGY: Yes (male and female main study only).
- tissues examined: adrenal glands, bone (sternum/femur), brain (cerebellum, cerebrum and cerebellum), epididymes, heart, kidneys, large intestine (caecum, colon and rectum), liver, lungs (with mainstream bronchi), lymph node (mesenteric), lymph node (mediastinal), mammary glands (with adjacent skin), ovaries (with oviducts), prostate, seminal vesicles, small intestine (duodenum, ileum and jejunum), spinal cord (cervical, thoracic and lumbar), spleen, stomach, testes, thymus, thyroids with parathyroids, tibial nerve, trachea, urinary bladder, uterus with vagina, all macroscopic lesions and tissue masses.
Postmortem examinations (offspring):
Macroscopic postmortem examinations (external only) were performed on all surviving F1 pups on lactation day 4.
Statistics:
Group mean values of parameters for all the exposure groups were compared to the control group mean values at each time interval, using appropriate statistical methods.

Evaluation of equality of group means was by made appropriate statistical method, followed by multiple comparison test if needed. Bartlett's test was used to determine if groups had equal variances. For all functional obeservation battery, clinical pathology, pre- and post-implantation loss parameters, if the variances were equal, parametric procedures were used, if not, non-parametric procedures were used. All other data was analysed only by parametric methods.

The parametric method was a standard one-way analysis of variance (ANOVA) using the F ratio to assess significance. If significant differences among the means were identified, additional tests were used to determine which means were significantly different from the control: Dunnett's, Williams or Cochran and Cox's modified t-test. The non-parametric method was a Kruskal-Wallis test and if differences were indicated, Shirley's test, Steel's test or a Pairwise Comparison was used to determine which means differed from controls. Bartlett's test for equality of variance was conducted at 1% significance level while all other statistical tests were conducted at 5% and 1% significance levels.

Statistical evalutaions were not performed when the standard deviation for the control group was 0. When 75% of the values for a clinical pathology parameter were the same, Fisher's Exact Test was performed followed by Mantel's tets.
Reproductive indices:
Male and female mating indices, pregnancy rates, male and female fertility indices, gestation indices and the incidence of dams with no viable pups, were analysed statistically.
Offspring viability indices:
Live birth index, litter survival and mean pup survival indices (days 0 and 4) were analysed statistically.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were some sporadic incidences of findings that are common to this strain of rat: predominantly localised patchy alopecia or staining, chromodacryonrrhea and maloccluded incisors (Table 1)
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
n/a
Mortality:
no mortality observed
Description (incidence):
n/a
Body weight and weight changes:
no effects observed
Description (incidence and severity):
n/a
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Marginally lower food consumption (6% difference) at 16000 ppm compared to controls was seen during 1st week of exposure, which was statistically significant for these females (Table 2).
Food efficiency:
not examined
Description (incidence and severity):
n/a
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
n/a
Ophthalmological findings:
not examined
Description (incidence and severity):
n/a
Haematological findings:
not examined
Description (incidence and severity):
n/a
Clinical biochemistry findings:
not examined
Description (incidence and severity):
n/a
Endocrine findings:
not examined
Description (incidence and severity):
n/a
Urinalysis findings:
not examined
Description (incidence and severity):
n/a
Behaviour (functional findings):
not examined
Description (incidence and severity):
n/a
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
n/a
Histopathological findings: non-neoplastic:
not examined
Description (incidence and severity):
n/a
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
n/a
Other effects:
not examined
Description (incidence and severity):
n/a

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Description (incidence and severity):
n/a
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
No abnormalities were evident in stages of spermatogenesis or testicular interstitial cells.
Reproductive performance:
no effects observed
Description (incidence and severity):
All mated females (except one each in the 5000 and 16000 ppm groups) were found pregnant and delivered live pups.
Mating indices for the males were comparable to control. Mating, fertility and gestation indices for females were comparable to control. All but one female mated at the first opportunity. For this pairing, in the 16000 ppm group, the female exhibited an irregular oestrous cycle during the mating period, there was no detected sign of mating and there was no pregnance.
There were no treatment-related differences in the other reproductive parameters up to time of parturition, including percentange of females completing delivery and duration of gestation. No effects on pre- or post-implantation loss, number of pups delivered, number of pups dying, the viability (4 day survival) index, the pup sex ratio and the number of live pups/litter.

Details on results (P0)

n/a

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEC
Remarks:
reproductive toxicity
Effect level:
16 000 ppm
Sex:
male/female
Basis for effect level:
other: highest concentration tested
Key result
Dose descriptor:
NOAEC
Remarks:
reproductive toxicity
Effect level:
19 678 mg/m³ air
Sex:
male/female
Basis for effect level:
other: highest concentration tested

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
not examined
Description (incidence and severity):
n/a
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
n/a
Mortality:
not examined
Description (incidence):
n/a
Body weight and weight changes:
not examined
Description (incidence and severity):
n/a
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
n/a
Food efficiency:
not examined
Description (incidence and severity):
n/a
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
n/a
Ophthalmological findings:
not examined
Description (incidence and severity):
n/a
Haematological findings:
not examined
Description (incidence and severity):
n/a
Clinical biochemistry findings:
not examined
Description (incidence and severity):
n/a
Endocrine findings:
not examined
Description (incidence and severity):
n/a
Urinalysis findings:
not examined
Description (incidence and severity):
n/a
Behaviour (functional findings):
not examined
Description (incidence and severity):
n/a
Immunological findings:
not examined
Description (incidence and severity):
n/a
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
n/a
Gross pathological findings:
not examined
Description (incidence and severity):
n/a
Neuropathological findings:
not examined
Description (incidence and severity):
n/a
Histopathological findings: non-neoplastic:
not examined
Description (incidence and severity):
n/a
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
n/a
Other effects:
not examined
Description (incidence and severity):
n/a
Details on results:
n/a

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not examined
Description (incidence and severity):
n/a
Reproductive function: sperm measures:
not examined
Description (incidence and severity):
n/a
Reproductive performance:
not examined
Description (incidence and severity):
n/a

Details on results (P1)

n/a

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
n/a
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
n/a
Mortality / viability:
no mortality observed
Description (incidence and severity):
n/a
Body weight and weight changes:
no effects observed
Description (incidence and severity):
n/a
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
n/a
Food efficiency:
not examined
Description (incidence and severity):
n/a
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
n/a
Ophthalmological findings:
not examined
Description (incidence and severity):
n/a
Haematological findings:
not examined
Description (incidence and severity):
n/a
Clinical biochemistry findings:
not examined
Description (incidence and severity):
n/a
Urinalysis findings:
not examined
Description (incidence and severity):
n/a
Sexual maturation:
not examined
Description (incidence and severity):
n/a
Anogenital distance (AGD):
not examined
Description (incidence and severity):
n/a
Nipple retention in male pups:
not examined
Description (incidence and severity):
n/a
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
n/a
Gross pathological findings:
no effects observed
Description (incidence and severity):
Scattered observations, such as no milk in stomach, were noted but they were not considered to be exposure related (Table 5).
Histopathological findings:
not examined
Description (incidence and severity):
n/a
Other effects:
not examined
Description (incidence and severity):
n/a

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined
Description (incidence and severity):
n/a

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined
Description (incidence and severity):
n/a

Details on results (F1)

No effects on total number of pups delivered, number of pups dying, viability (4 day survival) index, pup sex ratio or number of live pups/litter.

Effect levels (F1)

open allclose all
Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
16 000 ppm
Sex:
male/female
Basis for effect level:
other: highest concentration tested
Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
19 678 mg/m³ air
Sex:
male/female
Basis for effect level:
other: highest concentration tested

Results: F2 generation

General toxicity (F2)

Clinical signs:
not examined
Description (incidence and severity):
n/a
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
n/a
Mortality / viability:
not examined
Description (incidence and severity):
n/a
Body weight and weight changes:
not examined
Description (incidence and severity):
n/a
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
n/a
Food efficiency:
not examined
Description (incidence and severity):
n/a
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
n/a
Ophthalmological findings:
not examined
Description (incidence and severity):
n/a
Haematological findings:
not examined
Description (incidence and severity):
n/a
Clinical biochemistry findings:
not examined
Description (incidence and severity):
n/a
Urinalysis findings:
not examined
Description (incidence and severity):
n/a
Sexual maturation:
not examined
Description (incidence and severity):
n/a
Anogenital distance (AGD):
not examined
Description (incidence and severity):
n/a
Nipple retention in male pups:
not examined
Description (incidence and severity):
n/a
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
n/a
Gross pathological findings:
not examined
Description (incidence and severity):
n/a
Histopathological findings:
not examined
Description (incidence and severity):
n/a
Other effects:
not examined
Description (incidence and severity):
n/a

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined
Description (incidence and severity):
n/a

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined
Description (incidence and severity):
n/a

Details on results (F2)

n/a

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1
ETHANE: COMBINED REPEATED-EXPOSURE TOXICITY, REPRODUCTION AND NEUROTOXICITY SCREENING IN RATS VIA WHOLE-BODY INHALATION EXPOSURE
FEMALES SUMMARY OF CLINICAL OBSERVATIONS
  DAY OF STUDY
  GROUP# -7 0 7 14 21 28 35 42 49 54 TOTAL
# OF ANIMALS EXAMINED I 12 12 12 12 1 0 0 0 0 0
II 12 12 12 12 1 0 0 0 0 0
III 12 12 12 12 0 0 0 0 0 0
IV 12 12 12 12 2 2 2 1 1 1
Dermal-General
ALOPECIA - EXTREMITIES/SNOUT I 0 0 0 0 0 0 0 0 0 0 0
II 0 0 0 0 0 0 0 0 0 0 0
III 0 0 0 0 0 0 0 0 0 0 0
IV 0 0 0 0 0 0 0 0 1 0 1
RED/BROWN STAINS - EXTREMITIES/SNOUT I 0 0 0 0 1 0 0 0 0 0 1
II 0 0 0 0 0 0 0 0 0 0 0
III 0 0 0 0 0 0 0 0 0 0 0
IV 0 0 0 0 0 0 0 0 0 0 0
CHROMODACRYONRRHEA - UNILATERAL I 0 0 0 0 0 0 0 0 0 0 0
II 0 0 0 0 0 0 0 0 0 0 0
III 0 0 0 0 0 0 0 0 0 0 0
IV 0 0 0 1 0 0 0 0 0 0 1
Oral/Buccal
INCISORS MALOCCLUDED I 0 0 0 0 0 0 0 0 0 0 0
II 0 0 0 0 0 0 0 0 0 0 0
III 0 0 0 0 0 0 0 0 0 0 0
IV 0 0 0 1 0 0 0 0 0 0 1

Table 2
SUMMARY OF GESTATION FEED CONSUMPTION (GRAMS/KG/DAY)
  FEMALES
DOSE GROUP 1 2 3 4
  DOSE LEVEL (PPM) 0 1000 5000 16000
DAY 0 MEAN 100 98 99 96
SD 5.9 4.9 5.8 6.7
N 10 11 10 11
DAY 7 MEAN 88 86 84 83*
SD 3.9 4.2 3.5 5.1
N 10 11 11.0 10
DAY 14 MEAN 86 85 85 83
SD 3.4 5.2 5.3 4.2
N 10 11 11 11.0
Statistical key: * = p<0.05

Table 3
Summary statistics for absolute organ weights (g)
Group   Terminal Body wt. (g) Left Ovary
Female Animals
1 Mean 295.5 0.0902
SD 20.7 0.0142
N 12 12
2 Mean 297.2 0.0827
SD 22.6 0.0088
N 12 12
3 Mean 2861 0.0764
SD 23.5 0.0115
N 11 11
4 Mean 309.0 0.0821
SD 16.8 0.0148
N 11 11
Corresponding expsoure levels for each group were as follows:
Group 1 0 ppm
Group 2 1600 ppm
Group 3 5000 ppm
Group 4 16000 pm

Table 4
Incidence Summary Report for Gross Necropsy Observations
Females
Group 1 2 3 4
Number in group 12 12 12 12
Within normal limits 12 12 11 10
Colon Distended 0 0 0 1
Liver Adhesion 0 0 1 0
Ovaries Cyst 0 0 0 1
Diaphragm Herniated 0 0 1 0

Table 5
SUMMARY OF PUP NECROPSY OBSERVATIONS
  FEMALES
DOSE GROUP 1 2 3 4
  DOSE LEVEL (PPM) 0 1000 5000 16000
STOMACH
Litter Incidence N 3 2 2 1
Pup Incedence N 5 2 4 1
MILK IN STOMACH N 1 0 1 1
Pup Incedence % 0.6 0.0 0.6 0.6
N 1 0.0 1.0 1
Litter Incidence % 8.3 0.0 9.1 9.1
NO MILK IN STOMACH N 4 2 3 0
Pup Incedence % 2.2 1.2 1.8 0.0
N 2 2.0 2.0 0
Litter Incidence % 16.7 16.7 18.2 0.0

Applicant's summary and conclusion

Conclusions:
Inhalation exposure for up to 42 days had no effect on gestation duration, number of live and dead pups, pup abnormalities or pup sex and weights. The NOAEC for reproductive toxicity was 16000 ppm, equivalent to 19678 mg/m3.
Executive summary:

This OECD 422 study, the potential toxicity, including neurotoxicity and reproductive performance in male and female rats following ethane exposure at 1600, 5000 and 16000 ppm (highest exposure level was 50% of the lower explosive limit) were assessed. It also was designed to investigate effects in both sexes on mating behaviour and on gonadal function, as well as effects on conception, development, parturition and pup survival to lactation day 4.

Male and female rats were exposed for 6 hours/day, 7 days/week for 2 weeks prior to mating initiation. Main study females were evaluated for subchronic effects and were exposed once daily (6 hours/day), seven days/week for 4 weeks (28 days). A satellite group of females was evaluated for reproductive effects only - exposed once daily (6 hours/day), seven days/week for at least two weeks prior to mating initiation, then once daily during mating and gestation (days 0-19). For satellite female rats without evidence of mating that appeared to be pregnant, exposure was terminated on the estimated gestation day 19. Main study male rats were exposed during the mating and post-mating periods until euthanized for a minimum exposure of 28 days.

There was no effect on survival. There were no exposure-related clinical effects or effects on body weight, food consumption, FOB or motor activity parameters for either sex (except the16000 ppm exposed animals showed marginally lower food consumption during the first week of exposures).There were no exposure-related differences in haematology, clinical chemistry and no macroscopic or microscopic changes at post-mortem.

lmost all mated female animals were found pregnant and delivered live pups. Mating indices for the ethane male rats were comparable to control. Mating, fertility and gestation indices for the female rats were comparable to control. All but one of the females in each group mated at the first opportunity. There were also no treatment-related differences inthe other reproductive parameters up to the time of parturition including the percent offemales completing delivery and the duration of gestation. There were no exposure-related differences in any parturition parameters including pre-implantation loss, post-implantation loss, the total number of pups delivered, the number of pups dying, the viability (4 day survival) index, the pup sex ratio and the number of live pups/litter, when compared to the air control group.There were no exposure-related differences in body weights or weight gains in the pups feeding from ethane exposed females during gestation compared to the pups feeding from air control animals.There were no macroscopic changes at post-mortem.

Exposure of male and female rats to target concentrations of 1600, 5000 or 16000 ppm of ethane by whole-body inhalation for 4-6 weeks resulted in no general systemic/neurotoxic effects apart from a very marginal reduction of food consumption during the first week of exposure at 16000 ppm and this transient difference was not considered adverse. There were no effects on fertility or reproductive performance, including offspring survival and weight development up to post-natal day 4.

A no-observed-adverse effect concentration (NOAEC) of 16000 ppm was determined for all endpoints. Equivalent to 19678 mg/m3 (MW 30.07g/mol).