Butane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

The identity and stability was not in compliance with GLP regulations. The lot number was not available.

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: EPA 712-C-98-207 (August 1998)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

liquified petroleum gas

IUPAC Name:

liquified petroleum gas

Details on test material:

- Name of test material (as cited in study report): liquefied petroleum gas (LPG)
- Substance type: industrial gas
- Supplier: ChevronTexaco Energy Research & Technology Company, 100 Chevron Way, Richmond, CA 94802, USA
- Physical state: colourless gas or liquid in pressurized cylinders
- Analytical purity: 100% LPG
- Lot/batch No.: 120701-01
- Composition of test material, percentage of components (weight %): methane 0.012%, ethane 1.809%, propane & propylene 93.513%, n-butane 2.854%, n-pentane 0.064%, isobutane 1.246%, neopentane 0.003%, isopentane 0.404%, 2,3-dimethylbutane 0.006%, cyclopentane <0.001%, isobutene 0.038%, 1,3-butadiene <0.001%, t-2-butene 0.009%, c-2-butene 0.007%, 3-methyl-1-butene 0.004%, 1-pentene 0.014%, 2-methyl-1-butene 0.005%, t-2-pentene 0.003%, c-2-pentene 0.003%, 2-methyl-2-butene 0.005%, benzene <0.001%
- Storage condition of test material: Ambient conditions in an outside solvent shed except when in use in the inhalation laboratory.

Test animals

Species:

rat

Strain:

other: VAF/Plus®, Sprague-Dawley Derived (CD®) Crl:CD® IGS BR

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, North Carolina 27610, USA
- Age on gestation day 0: 70-84 days
- Weight on gestation day 0: 225-250 g
- Fasting period before study: none
- Housing: individually in stainless steel suspended cages with wire mesh floors and fronts
- Diet: Certified Rodent Diet, No. 5002 (PMI Nutrition International, St Louis, Missouri, USA) ad libitum except during exposures
- Water: Municipal drinking water ad libitum (except during exposures)
- Acclimation period: 4-6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22-24°C
- Humidity: 14-60%
- Air changes: 10-15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 22 February 2005 To: 11 March 2005

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: air

Details on exposure:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, North Carolina 27610, USA
- Age on gestation day 0: 70-84 days
- Weight on gestation day 0: 225-250 g
- Fasting period before study: none
- Housing: individually in stainless steel suspended cages with wire mesh floors and fronts
- Diet: Certified Rodent Diet, No. 5002 (PMI Nutrition International, St Louis, Missouri, USA) ad libitum except during exposures
- Water: Municipal drinking water ad libitum (except during exposures)
- Acclimation period: 4-6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22-24°C
- Humidity: 14-60%
- Air changes: 10-15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 22 February 2005 To: 11 March 2005

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Exposure levels analysed 4 times/chamber/day. Mean ± SD analytical concentrations were 0±0, 1013±60, 5079±217 and 10,426±527 ppm for controls, 1000, 5000 and 10,000 ppm respectively. Particle sizing indicated the atmospheres were gas/vapour only. Analysis of major components in the neat test substance and the vaporised test substance were acceptably close and the test substance was confirmed to be stable.

Details on mating procedure:

- Impregnation procedure: purchased timed pregnant

Duration of treatment / exposure:

gestation days 6-19

Frequency of treatment:

7 days/week for 6 hours/day

Duration of test:

animals received on gestation days 0, 1 or 2; experimental start (1st day of exposure) gestation day 6, terminal sacrifice gestation day 20

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 1000, 5000, 10,000 ppm
Basis:
other: target concentrations

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0±0, 1100±32, 5000±113, 9800±131 ppm
Basis:
analytical conc.

No. of animals per sex per dose:

24

Control animals:

other: exposed to air only

Details on study design:

- Dose selection rationale: based on a range-finding study which showed no effects at 100, 1000 or 10,000 ppm and the upper exposure concentration was less than 50% of the lower explosion limit (LEL = 2.1% = 21,000 ppm)
- Rationale for animal assignment (if not random): randomly assigned

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily
- Cage side observations checked: mortality and viability

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: out-of-chamber daily from receipt until gestation day 20. In-chamber: at least once during each exposure as a group.
- Out-of-chamber examinations comprised: general condition, skin and fur, eyes, nose, oral cavity, abdomen and external genitalia, occurrence of secretions and excretions and autonomic activity (lachrymation, piloerection, pupil size, unusual respiratory pattern), changes in gait, posture and response to handling as well as presence of repetitive circling or bizarre behaviour (self-mutilation, walking backwards).

BODY WEIGHT: Yes
- Time schedule: gestation days 3, 6, 9, 12, 15, 18 and 20

FOOD CONSUMPTION: Yes
- Time schedule: gestation days 3-6, 6-9, 9-12, 12-15, 15-18 and 18-20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Intact uteri (ovaries attached) were removed from the abdominal cavity. The gravid uteri, including the cervix, were weighed. Corpora lutea were counted and the number per ovary recorded. The number and location of the following were recorded for each uterine horn: live foetuses, late embryo-foetal deaths, early embryonic deaths. Each placenta was examined macroscopically.

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 per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter

Statistics:

Continuous maternal parameters, % pre-implantation loss and % total resorptions/implant sites: If Bartlett's test significant at 1% level, a Kruskal-Wallis test and if significant at 5% level, Steel's test. If Bartlett's test not significant at 1% level, one-way analysis of variance and if significant at 5% level Dunnett's test.
Litter size: analysed using a generalised linear model. If significant, compared using pairwise tests on the least squares means.
Corpora lutea, number of implant sites, early, late and total resorptions, numbers of males and females: as for litter size except the means were adjusted for litter size.
Foetal bodyweight: mixed model of variance with dose group and foetal sex and their interaction as explanatory variables and litter size as covariate. If significant at 5% level, Dunnett's test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Effect levels (maternal animals)

1

Dose descriptor:

NOAEC

Effect level:

10 426 ppm (analytical)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEC

Effect level:

10 426 ppm (analytical)

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

There were no effects on maternal survival, clinical observations, body weight or food consumption. There were no effects on corpora lutea numbers, pre- or post-implantation loss, litter size or gravid uterus weight. There were no effects on foetal bodyweights, foetal variants or abnormalities or on the state of ossification of the foetal skeleton.

Applicant's summary and conclusion

Conclusions:

The no observed adverse effect concentration (NOAEC) of liquified petroleum gas for maternal and developmental toxicity to rats was 10,000 ppm.

Executive summary:

Exposure of pregnant rats to target concentrations of 1000, 5000 or 10,000 ppm liquified petroleum gas by whole-body inhalation on gestation days 6 -19 resulted in no effects of exposure. Therefore, a no observed adverse effect concentration (NOAEC) for maternal toxicity and developmental toxicity of 10,000 ppm was indicated.