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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:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to guideline standards in context of the National Toxicology Program with detailed decription
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2009

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
yes
Remarks:
Batelle Toxicology Northwest (Richland, WA)
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Cumene

- Substance type:
- Physical state: colorless liquid with a sharp, penetrating, aromatic odour
- Analytical purity: 99.9% peak area
- Impurities (identity and concentrations): No impurities >0.05% peak area detected
- Purity test date: Not specified
- Lot/batch No.: Lot 200556852
- Expiration date of the lot/batch: No data
- Stability under test conditions: stable over the test period, no degradation of bulk chemical was detected

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Laboratory Animals and Services (Germantown, NY)
- Age at study initiation: approx. 6 weeks old on first day of study
- Weight at study initiation: 19.0+/-0.2 to 23.4 +/- 0.3 g
- Fasting period before study:
- Housing: individually
- Diet (e.g. ad libitum): NTP-2000 irradiated pelleted diet (Zeigler Brothers, Inc, Gardeners, PA); changed weekly
- Water (e.g. ad libitum): Tap water (Richland, WA, muncipal supply) via automatic watering system (Edstrom Industries, Waterford, WI)
- Acclimation period: 11 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 2 (75 +/- 2° F)
- Humidity (%): 55 +/- 15
- Air changes (per hr): 15 +/- 2
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: gas
Vehicle:
- Vehicle(s)/solvent(s) used: unchanged (no vehicle)
Duration of treatment / exposure:
6 h plus T90 (=12 min)
Frequency of treatment:
5 days per week (excluding holidays) for 14 weeks
Post exposure period:
none
Doses / concentrations
Remarks:
Doses / Concentrations:
62.5, 125, 250, 500, and 1000 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
9-10
Control animals:
yes, concurrent vehicle
Positive control(s):
none

Examinations

Tissues and cell types examined:
blood smears from peripherial blood.
Details of tissue and slide preparation:
Smears were immediately prepared and fixed in absolute methanol.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not examined
Positive controls validity:
not examined
Additional information on results:
No increase in micronucleated erythrocytes was observed in peripheral blood of male or female mice exposed to cumene by inhalation (62.5 to 1,000 ppm) for 3 months. For both male and female mice, no significant changes in the percentage of PCEs were observed over the exposure range tested, indicating an absence of treatment-related toxicity to the bone marrow.

RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei (for Micronucleus assay): see table below
- Ratio of PCE/NCE (for Micronucleus assay): see table below
- Statistical evaluation: see table below

Any other information on results incl. tables

Frequency of Micronuclei in Peripheral Blood Erythrocytes of Mice Following Treatment with Cumene by Inhalation for 3 Months[a]

Compound

Dose (ppm)

Number of male rats with erythrocytes scored

Micronucleated PCEs/ 1000 PCEs [b]

Pairwise P value [c]

PCE [b] (%)

Male

Air [d]

0

10

2.40 ± 0.69

2.7 ± 0.1

Cumene

62.5

10

2.20 ± 0.66

0.6161

2.6 ± 0.1

125

10

2.10 ± 0.48

0.6728

2.6 ± 0.1

250

10

1.80 ± 0.36

0.8230

2.8 ± 0.1

500

10

2.00 ± 0.26

0.7270

2.9 ± 0.1

1,000

10

2.20 ± 0.42

0.6161

2.9 ± 0.2

P=0.553 [e]

Female

Air

0

10

2.30 ± 0.40

3.3 ± 0.1

Cumene

62.5

9

1.33 ± 0.37

0.9396

2.3 ± 0.1

125

10

1.70 ± 0.30

0.8289

3.1 ± 0.2

250

10

2.10 ± 0.53

0.6186

3.3 ± 0.2

500

10

2.10 ± 0.35

0.6186

3.4 ± 0.1

P=0.329

[a] Study was performed at ILS, Inc. The detailed protocol is presented by MacGregor et al. (1990).

NCE=normochromatic erythrocyte; PCE=polychromatic erythrocyte

[b] Mean ± standard error

[c] Pairwise comparison with the chamber controls, significant at P#0.025 (PCEs) or P#0.005 (NCEs) (ILS, 1990)

[d] Chamber control

[e] Significance of micronucleated NCEs/1,000 NCEs tested by the one-tailed trend test, significant at P#0.025 (ILS, 1990)

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
No increase in micronucleated erythrocytes was observed in peripheral blood of male or female mice exposed to cumene by inhalation for 3 months.
Executive summary:
No increase in micronucleated erythrocytes was observed in peripheral blood of male or female mice exposed to cumene by inhalation (62.5 to 1,000 ppm) for 3 months. For both male and female mice, no significant changes in the percentage of PCEs were observed over the exposure range tested, indicating an absence of treatment-related toxicity to the bone marrow.