Cumene

Genetic toxicity: in vivo

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 for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

GLP compliance:

yes

Remarks:

Batelle Toxicology Northwest (Richland, WA)

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

Cumene

EC Number:

202-704-5

EC Name:

Cumene

Cas Number:

98-82-8

Molecular formula:

C9H12

IUPAC Name:

isopropylbenzene

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 or test system 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.