Cumene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study similar to guideline with full report available.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1989

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1992

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes

Remarks:

Research Triangle Institute

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
- Analytical purity: 99.95%
- Impurities (identity and concentrations): Not reported
- Lot/batch No.: Tank 938, Chevron Chemical Company
- Radiochemical purity (if radiolabelling): 98%
- Specific activity (if radiolabelling): Not reported
- Locations of the label (if radiolabelling): [phenyl-14C]cumene

Radiolabelling:

yes

Remarks:

;[phenyl-14C]cumene

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 7-9 weeks
- Weight at study initiation: 80-190g
- Fasting period before study: Not reported
- Housing: cohoused prior to exposure, 4 animals per cage
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): yes, certified purina rat chow
- Water (e.g. ad libitum): yes, tap water
- Acclimation period: 48 h, 7 d quarantine time in cohoused conditions


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23°C
- Humidity (%): 50+-20%
- Air changes (per hr): 10-15 per hr
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: nose only

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Cumene was evaporated at 60°C in a glass tube with glass beads. The cumene vapour was delivered via teflon and stainless steel tubing to individual nose-ports
- Method of holding animals in test chamber: Batelle adjustable rat restrainer
- Source and rate of air: Room air
- Method of conditioning air: Not reported except that air was heated up to 60°C

Duration and frequency of treatment / exposure:

6 h

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 500, 1200 ppm (nominal), 104+-6, 494+-3, 1194+-67 ppm (measured)

No. of animals per sex per dose / concentration:

4+1

Control animals:

no

Positive control reference chemical:

Not performed

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, expired breath, cage rinse
- Time and frequency of sampling: 8, 16, 24, 48 and 72 h after start of exposure
- Other:

DISTRIBUTION STUDIES:
- Tissues and body fluids sampled: adipose tissue, femur, brain, heart, kidney liver, lung, spleen, skeletal muscle, gonads, carcass
- Time and frequency of sampling: 72 h after start of exposure
- Other:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, expired breath
- Time and frequency of sampling: pooled samples 0-24 h and 24-48 h
- From how many animals: pooled samples by sex and concentration
- Method type(s) for identification: HPLC, Liquid scintillation counting, Comparison of retention times with known substances, Enzymatic treatment (ß-glucuronidase, sulfatase)
- Limits of detection and quantification: Not reported
- Other:

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Cumene was absorped rapidly from the lung, with detectable levels found to be present in the blood within 5 min of the start of exposure. Cumene concentration in blood reached a peak after 6 hours of exposure and decreased after the end of exposure (first analysed 2h after). The overall absorption is about 100% based on the comments in the excreta (see below).
Half-life of disappearance from the blood at:
100 ppm: 3.9 +- 0.7 h
500 ppm: 4.6 +- 0.7 h
1200 ppm: 6.6 +- 1.3 h.

Details on distribution in tissues:

Generally concentrations in the tissues are low as >90% were excreted. Adipose tissues was observed to have slightly elevated concentrations at all doses, followed by liver and kidney. Further, elevated levels were detected in bone and muscle. There is no indication that cumene or its radioactive metabolites accumulate in any tissue.

Details on excretion:

After nose-only inhalation of cumene urine was found to be the predominant route of excretion. Excretion was rapid with the majority of cumene being excreted with 24 h (78.6 to 84.6%) and after 72% nearly complete excretion was observed (96.0 to 98.9%). Urine was the major route of elimination (76.2 to 93.2%). Elimination via faeces was only of minor importance with 1.5 to 4.8%. At the highest concentration of 1200 ppm excretion via expired breath increases and in male and female resulted in 8.4 and 17.5% of the absorbed cumene, respectively.
Half-life for excretion:
100 ppm: could not be determined
500 ppm: 17 h
1200 ppm: 30 h

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Six unknown radiolabelled metabolites were detected by HPLC. After treatment with glucuronidase and sulfatase, the following metabolites were identified: The major metabolite of urinary excretion (50% and more) was 2-phenyl-2-propanol and its glucuronide and/or sulphate conjugates (Metabolites 6) . Metabolites 1, 4, and 5 were converted to free 2-phenyl-1,2-propanediol. Metabolite 2 was unaffected by deconjugating enzymes. For metabolite 3 also no change was observed. However, this metabolite occured only in a minimal extent. Afterwards an in-depth analysis using 13C- and 1H-NMR spectroscopy resulted in two compounds. One of the two was identified to be phenylmalonic acid. The identity of the second compound could not be verified. Based upon retention time the metabolites were the same after iv, oral and inhalation exposure.

Any other information on results incl. tables

Concentration of cumene in blood, measured over 48 h [µg/g blood]

Time	100 ppm		500 ppm		1200 ppm
	Male	Female	Male	Female	Male	Female
5min	0.6	0.6	2.9	4.8	3.6	5.8
10min	1.0	0.8	2.7	6.8	7.1	9.8
15min	0.9	0.9	5.1	4.6	11.1	12.8
30min	1.0	1.1	4.3	4.3	17.8	17.2
1h	1.8	1.5	6.0	5.8	21.9	25.9
2h	1.6	1.9	11.0	8.4	40.7	50.0
4h	1.7	1.9	12.4	16.0	41.4	63.4
6h	4.3	4.4	17.1	20.9	59.5	82.4
8h	1.1	2.4	4.8	5.7	38.0	41.1
16h	1.5	1.9	0.9	1.0	2.5	2.2
24h	1.9	1.7	0.6	0.7	0.9	0.9
48h	1.4	0.9	0.4	0.4	0.5	0.5

Distribution into tissues [% dose in total tissue]

	100 ppm		500 ppm		1200 ppm
	Male	Female	Male	Female	Male	Female
Adipose	0.04	0.03	0.08	0.06	0.05	0.02
Blood	0.03	0.02	0.01	0.01	0.01	<0.005
Bone	0.03	0.07	0.01	0.01	0.02	0.01
Brain	<0.005	<0.005	<0.005	<0.005	<0.005	<0.005
Heart	<0.005	<0.005	<0.005	<0.005	<0.005	<0.005
Kidney	<0.005	0.01	<0.005	<0.005	<0.005	<0.005
Liver	0.03	0.02	0.02	0.01	0.01	0.01
Lung	<0.005	<0.005	<0.005	<0.005	<0.005	<0.005
Muscle	0.12	0.15	0.13	0.12	0.10	0.07
Plasma	<0.005	<0.005	<0.005	<0.005	<0.005	<0.005
Spleen	<0.005	<0.005	<0.005	<0.005	<0.005	<0.005
Testis	<0.005		<0.005		<0.005
Ovary		<0.005		<0.005		<0.005
Carcass	2.68	3.64	0.87	2.93	1.57	0.98

Excretion after 72 h [% of absorbed]

	Total	Urine	Feces	CO2 Breath	Volatile Breath
100 ppm
Male	97.1	93.1	1.5	0.2	2.3
Female	96.0	91.1	2.0	0.2	2.8
500 ppm
Male	98.9	93.2	2.0	0.2	3.4
Female	96.9	86.4	3.2	0.2	7.0
1200 ppm
Male	98.2	87.2	2.5	0.2	8.4
Female	98.9	76.2	4.8	0.2	17.3

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Cumene is absorbed well by nose-only inhalation exposure. Following absorption, cumene is metabolized and excreted, mostly via urine. There is no evidence for accumulation of cumene.

Executive summary:

Rats were exposed nose-only for 6 h to cumene concentrations of 100, 500, and 1200 ppm. 4 rats were investigated per concentration. [14C]cumene was used to investigate absorption, excretion, tissue distribution as well as metabolism. Cumene was rapidly absorbed through the lungs. Main excretion pathway is via urine. After 72 h cumene was ecreted nearly completely from the body, with the majority excreted after 24h. Distribution into tissues was broad and elevated levels was found in adipose tissue and liver and kidney. This was expected form the lipophilictiy of the substance as well as the fact that cumene undergoes oxidative metabolism located in liver and kidney. The major metabolite of urinary excretion was 2-phenyl-2-propanol and its glucuronide and/or sulphate conjugates..