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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
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other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

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)
Deviations:
no
Principles of method if other than guideline:
Guideline study
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Hydrocarbons, C4, ethylene-manuf.-by-product
EC Number:
270-691-3
EC Name:
Hydrocarbons, C4, ethylene-manuf.-by-product
Cas Number:
68476-52-8
IUPAC Name:
Hydrocarbons, C4, ethylene-manuf.-by-product
Constituent 2
Reference substance name:
C4 Crude Butadiene (low 1,3-Butadiene Content)
IUPAC Name:
C4 Crude Butadiene (low 1,3-Butadiene Content)
Constituent 3
Reference substance name:
25167-67-3, 64742-83-2, 68187-60-0, 68476-44-8, 68955- 28-2, 68956-54-7
IUPAC Name:
25167-67-3, 64742-83-2, 68187-60-0, 68476-44-8, 68955- 28-2, 68956-54-7
Details on test material:
- Name of test material (as cited in study report): C4 Crude Butadiene (low 1,3-Butadiene Content)
- Supplier: Texas Petrochemicals, LP
- Substance type: Chemical stream
- Physical state: vapour
- Composition of test material, percentage of components: approx. composition: 10% 1,3-butadiene, 4% isobutane, 4% n-butane, 29% trans-2-butene, 29% 1-butene, 11% isobutylene, 12% cis-2-butene
- Lot/batch No.: lot # 268193
- Storage condition of test material: Supplied in cylinders and stored at approximately 4°C in an enclosed storage building, and kept at approximately 16°C during use.

Test animals

Species:
rat
Strain:
other: Crl:CD® (Sprague-Dawley) IGS BR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan< USA
- Age at study initiation: Approximately 8 weeks
- Weight at study initiation: Approximately 200-300 g (males) and 155-225 g (females)
- Housing: one per cage in stainless steel cages
- Diet: LabDiet® Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in meal form ad libitum (except during exposures).
- Water: Municipal water ad libitum (except during exposures)
- Acclimation period: At least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 40-70%
- Air changes: 12-15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 24 October 2000 To: 29 November 2000

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 2 m3 stainless steel and glass Rochester-style exposure chambers (1.3m tall x 1.2m wide x 1.2m deep with a pyramidal top and bottom).
- Method of holding animals in test chamber: in stainless steel cages within the exposure chamber
- Temperature, humidity in air chamber: 21.20 ± 1.67, 21.42 ± 0.46, 20.59 ± 0.47, 22.06 ± 0.49°C for 0, 2, 10 and 20 mg/L exposure groups respectively / 46.01 ± 3.36, 53.41 ± 6.93, 51.25 ± 7.86, 39.94 ± 7.32% for 0, 2, 10 and 20 mg/L exposure groups respectively.
- Air flow rate: approximately 450 L/minute
- Air change rate: 12-15 calculated air changes per hour.

TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatography
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The distribution of total hydrocarbons within the five sample locations in each chamber ranged from 91.35 to 104.94% of the mean reference value. The analytical concentrations for each chamber were 0.0, 2.17, 9.81 and 19.1 mg/L for the targeted concentrations of 0, 2, 10, and 20 mg/L, respectively
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: until pregnancy occurred or 2 weeks
- Proof of pregnancy: vaginal plug / sperm in vaginal lavage referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged individually
Duration of treatment / exposure:
Two weeks prior to breeding, during breeding (up to two weeks), and continuing through day 19 of gestation. The dams were then allowed to deliver their litters, which were retained until postnatal day 4.
Frequency of treatment:
6 hours/day, 7 days/wk
Duration of test:
Two weeks prior to breeding, during breeding (up to two weeks), and continuing through day 19 of gestation. The dams were then allowed to deliver their litters, which were retained until postnatal day 4.
No. of animals per sex per dose:
12
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: The high-exposure concentration of 20 mg/L was chosen based upon data from previous studies with a similar material. This concentration was approximately 50% of the lower explosive limit, which exceeded a limit test as defined for 90-day, repeated-dose inhalation toxicity studies in U.S. EPA OPPTS Guideline 870.3465. The lower-exposure concentrations were selected to provide exposure-response data for any toxicity that may be observed among the high-exposure group rats and to establish a no-observable-effect level (NOEL).

Examinations

Maternal examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: skin, fur, mucous membranes, respiration, nervous system function (including tremors and convulsions), animal behaviour, moribundity, mortality, and the availability of feed and water, clinical examinations were conducted on all females pre-exposure and weekly throughout the pre-breeding and breeding periods. Mated (sperm positive or plug positive) females received clinical examinations on gestation day (gd) 0, 7, 14, and 21. Females that delivered litters were subsequently evaluated on lactation day (ld) 0, 1, and 4. Females that failed to mate or failed to deliver litters were examined weekly. This examination included a careful, hand-held evaluation of the skin, fur, mucous membranes, respiration, nervous system function (including tremors and convulsions), swelling, masses, and animal behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: at least once during the pre-exposure period and on the first day of exposure. Females were weighed weekly during the pre-mating and mating periods. During gestation, females were weighed on days 0, 7, 14, and 20. Females that delivered litters were weighed on days 1 and 4 of lactation. Females that failed to mate or deliver a litter were not weighed during the gestation or lactation phases. Body weight gains were determined for the females on gestation days 0-7, 7-14, 14-20, 0-20, and lactation days 1-4.

FOOD CONSUMPTION: Yes
- Time schedule: For females, weekly during the pre-breeding period, not measured during the mating period, following mating, gestation days 0-7, 7-14, 14-20, and on lactation days 1-4. Feed consumption was not recorded for females that failed to mate or deliver a litter.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- females that delivered litters were fasted overnight on day 4 of lactation and necropsied the following day. Satellite females for which there was no evidence of successful breeding were necropsied 17 days after the last day of the mating period.

ORGAN WEIGHTS: Yes (brain, liver, kidney, lungs
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
Fetal examinations:
All pups surviving to lactation day 4 were examined for gross external alterations, euthanized by oral administration of sodium pentobarbital solution, and then discarded. Any pups found dead were examined to the fullest extent possible.
Statistics:
Adult body weights and feed consumption, maternal body weight gains, and pup body weights were analyzed by ANOVA. Gestation length, average time to mating (precoital interval) and litter size were analyzed using a nonparametric ANOVA. Pregnancy rates and mating, conception, fertility and gestation indices were analyzed by the Fisher exact probability test. Evaluation of the neonatal sex ratio was performed by the binomial distribution test. Post-implantation loss, pup survival indices, and other incidence data among neonates were analyzed using the litter as the experimental unit by a censored Wilcoxon test.
Indices:
not given
Historical control data:
none

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
there was no maternal toxicity

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Effect level:
20 other: mg/L air (20,000 mg/m3)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
20 other: mg/L air (20,000 mg/m3)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
no embryotoxicity

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
20 other: mg/L air (20,000 mg/m3)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

There were no deaths or treatment-related clinical observations noted. No significant differences in parental body weights, body weight gains or feed consumption were observed at any dose level tested throughout the duration of the study. There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study. These included measures of reproductive performance (mating, conception and fertility, time to mating, gestation length, litter size), offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. The only statistically identified change in any of these parameters was an increase in post implantation loss occurring only at the low-dose. This was considered a spurious finding, given the lack of a dose response. Of the 12 females mated in each group, the number of viable litters produced was 11, 11, 11, and 12 for the 0, 2, 10 and 20 mg/L exposure level groups, respectively. External morphological alterations observed in the pups were limited to a hernia observed in a single pup from the high dose group. Given the low incidence of this finding, it was considered to be a spontaneous finding unrelated to exposure.

Applicant's summary and conclusion

Conclusions:
Repeated inhalation exposure of C4 Crude Butadiene, to male and female rats at levels up to 20 mg/L produced no evidence of adverse effects on developmental toxicity or teratogenicity.
Executive summary:

Male and female Sprague Dawley rats were exposed to C4 Crude Butadiene by inhalation at levels of 0, 2, 10, or 20 mg/L (6h/day, 7 d/week) for two weeks prior to breeding, during breeding (up to two weeks), and through day 19 of gestation. After birth, pups were maintained until postnatal day 4. There was no treatment-related maternal toxicity or effects on developmental toxicity or teratogenicity. Based on these data, the NOAEC for reproductive toxicity was 20 mg/L (20,000 mg/m3), the highest concentration tested.