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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP status unknown, near guideline study, published in peer reviewed literature, adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Chloroprene and isoprene: cytogenetic studies in mice
Author:
Tice RR et al
Year:
1988
Bibliographic source:
Mutagenesis 3 (2), 141-146

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
not specified
Type of assay:
micronucleus assay

Test material

Constituent 1
Reference substance name:
Isoprene
EC Number:
201-143-3
EC Name:
Isoprene
Cas Number:
78-79-5
IUPAC Name:
isoprene
Constituent 2
Reference substance name:
2-methyl-1,3-butadiene
IUPAC Name:
2-methyl-1,3-butadiene
Details on test material:
Purity > 98% (Goodyear Tire and Rubber Co., Akron, OH, USA)

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: National Toxicology Program's production colonies (Simonsen Laboratories, Gilroy, CA, USA)
- Age at study initiation: 5-7 week
- Housing: Individually in polycarbonate cages for the first 5 days and in stainless steel racks in Hazleton 2000 inhalation chambers thereafter.
- Diet: ad libitum (except during exposure)
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 20-24°C
- Humidity: 50 ± 15%
- Air changes (per hr): no data
- Photoperiod: 12(hrs dark / 12hrs light

IN-LIFE DATES: not reported

Administration / exposure

Route of administration:
inhalation
Vehicle:
Vehicle(s)/solvent(s) used: air
Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body

TEST ATMOSPHERE
- Brief description of analytical method used: The chamber concentration of isoprene was monitored at 30 min intervals by gas chromatography to a detection limit of 0.02 ppm.
Duration of treatment / exposure:
6 hours/day for 12 days
Frequency of treatment:
3 exposure days, followed by 2 non-exposure days, followed by 5 exposure days, followed by 2 non-exposure days, followed by 4 exposure days.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 438, 1750, 7000 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
15
Control animals:
yes, sham-exposed

Examinations

Statistics:
The number of micronucleated erythrocytes (MN) were summed across animals within each group and analyzed for increasing trend by a one-tailed trend test (p<0.05). For data exhibiting a significant trend, pairwise comparisons between each exposure group and the concurrent control were performed using a one-tailed Pearson Chi square test to determine the minimal effective dose.

Results and discussion

Test results
Sex:
male
Genotoxicity:
positive

Any other information on results incl. tables

NOAEL (NOEL): < 438 ppm
LOAEL (LOEL):
 438 ppm

Exposure to isoprene for 6 h/day for 12 days induced a statistically significant increase in the frequency of MN-PCEs and NCEs in male mice at all exposure levels tested.
 The frequencies of MN-PCEs were 2.00, 12.00, 15.60 and 16.93 at 0, 438, 1750, and 7000 ppm. The responses at the 1750 and 7000 ppm levels both were greater than the 438 ppm level, but not statistically different from each other. There also was a dose-related decrease in the percentage of PCEs, a measure of the rate erythropoiesis (3.91, 3.00, 2.87, and 1.64 at 0, 438, 1750 and 7000 ppm). There were no significant clinical signs or mortality.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): positive
Isoprene was found to be genotoxic to mouse bone marrow in vivo by inducing increased MN in the peripheral blood of male mice. Suppression of erythropoiesis was suggested by decreased percentage of PCEs.
Executive summary:

Groups of 15 male B6C3F1 mice were exposed for 6 hour/day for 12 days to 0, 438, 1750 and 7000 ppm isoprene. Exposure to isoprene induced significant increases at all concentrations in the levels of micronucleated polychromatic erythrocytes (PCE) and of micronucleated normochromoatic erythrocytes in peripheral blood. In addition, a significant lengthening of the bone marrow average generation time and a significant decrease in the percentage of circulating PCE was detected. The dose-response curve for micronuclei induction was non-linear, appearing to saturate at 1750 ppm.

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