Hydrocarbons, C4-12, naphtha-cracking, hydrotreated

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, non-guideline animal experimental study, available as unpublished report, no restrictions, fully adequate for assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats were exposed to cyclohexane by the dermal and intravenous routes, exposure was compared.

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Cyclohexane

EC Number:

203-806-2

EC Name:

Cyclohexane

Cas Number:

110-82-7

Molecular formula:

C6H12

IUPAC Name:

cyclohexane

Details on test material:

Non-radiolabelled
- Name of test material (as cited in study report): cyclohexane
- Analytical purity: Analysed but not reported
- Supplied by: DuPont, Newark, DE, USA.
- Lot/batch No.: H-21174, H-21,174
- Storage condition of test material: Room temperature

Radiolabelled
- Supplied by: Wizard Laboratories, Inc., West Sacramento, CA, USA.
- Chemical purity: 99.5%
- Physical state: liquid
- Lot/batch No.: 950712
- Radiochemical purity (if radiolabelling): >=98%
- Specific activity (if radiolabelling): 10.46 mCi/mmol
- Storage condition of test material: Approximately -20C

Radiolabelling:

yes

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, Inc., Raleigh, NC and Kingston, NY, USA.
- Age at study initiation: Males 10-11 weeks, females 10-12 weeks
- Weight at study initiation: Males 211-247 g, females 146-168 g
- Housing during the metabolism experiments: Individually in all glass Roth-Type metabolism chambers which provided for separate collection of urine, faeces, and expired volatiles. Animals were acclimated for a minimum of 24 h prior to the initiation of the study.
- Diet: Purina Certified Rodent Chow (#5002) ad libitum
- Water: Tap water ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18-26°C
- Humidity: 40-70 %
- Air changes: 10-15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: Intralipid for IV, no vehicle for dermal

Duration of exposure:

Dermal exposure for 6 h

Doses:

Nominal doses: Dermal exposure - 1 mg/cm2 (approximately 6 mg/rat) and 100 mg/cm2 (approximately 600 mg/rat); IV bolus - 10mg/kg

No. of animals per group:

IV bolus: 5/sex
Dermal: 6/sex

Control animals:

no

Details on study design:

Intravenous administration:
Bolus injection into a lateral tail vein.

Dermal exposure:
The test site was clipped approximately 24 h prior to dosing and a non-absorptive containment appliance was bonded to the rat's skin using super glue. The dose was applied to the 6cm2 area of clipped skin within the containment appliance. At the end of the exposure period, the unabsorbed cyclohexane was recovered from the containment appliance.

Biological sampling:
Urine, faeces and exhaled organics were collected separately over timed intervals for up to 72 h after dosing and analysed for radioactivity. Blood samples were taken from a separate group of animals at intervals for determination of radioactivity. Following sacrifice, adipose samples were removed and the remaining carcass solubilised for determination of radioactivity. Additionally for the dermally exposed animals, the dose site skin was removed and solubilised and analysed for radioactivity.

Sample Analysis:
All samples were analysed for total radioactivity by liquid scintillation counting.

Results and discussion

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

Dermal absorption
1mg/cm2: Male; 39%, Female; 60%
100mg/cm2: Male and female; 4%

Total recovery:

1mg/cm2: Male; 80±12%, Female; 82±16%
100mg/cm2: Male; 97±2, Female; 99±1%

Any other information on results incl. tables

Cyclohexane was rapidly excreted after either intravenous or dermal administration. Expired breath was the major route of excretion of radiolabel accounting for ca. 70% of the excreted radiolabel following intravenous administration of cyclohexane, ca. 78% of the excreted radiolabel following dermal exposure to cyclohexane at 1 mg/cm², and ca. 57% of the excreted radiolabel following dermal exposure to cyclohexane at 100 mg/cm². Urine was a lesser route of excretion of radiolabel, accounting for ca. 29% of the excreted radiolabel following intravenous administration of cyclohexane, ca. 20% of the excreted radiolabel following dermal exposure to cyclohexane at 1 mg/cm², and ca. 40% of the excreted radiolabel following dermal exposure to cyclohexane at 100 mg/cm². Essentially no radiolabel was excreted in faeces following either intravenous or dermal administration of [¹⁴C]cyclohexane.

 

Male rats and female rats absorbed approximately 39% and 60%, respectively, of the 1 mg/cm²dermal dose of cyclohexane. The average absorption rates of cyclohexane were 0.06 and 0.1 mg/cm² of exposed skin/h for male rats and female rats, respectively. Exposure at this dose level was primarily to cyclohexane vapours. These values are averages of the absorption calculated by three different methods: total excretion and residual body burden of radiolabel following the dermal dose; relative urinary excretion of radiolabel following dermal and intravenous doses of [¹⁴C]cyclohexane; and relative AUCo for total radiolabel in blood following dermal and intravenous doses of [¹⁴C]cyclohexane.

 

Increase of the dermal dose by two orders of magnitude (from 1 to 100 mg/cm) produced only a ca. one order of magnitude increase in the rate of absorption of cyclohexane.

 

Both male rats and female rats absorbed approximately 4% of the 100 mg/cm² dermal dose of cyclohexane. The average absorption rates of cyclohexane were 0.6 and 0.7 mg/cm² of exposed skin/h for male rats and female rats, respectively. Exposure was primarily to cyclohexane liquid present as an "infinite dose". Values are averages calculated as described for the 1 mg/cm² dermal dose.

 

The areas under the concentration of total radiolabel in blood vs. time curves AUC(0 - ∞) were similar for male and female rats following intravenous administration of [¹⁴C]cyclohexane. The AUC(0 - ∞) values following dermal exposure to cyclohexane were ca. 3 times greater for females than for males at the 1 mg/cm² exposure level and ca. 2 times greater for females than for males at the 100 mg/cm² exposure level. Thus there appear to be quantitative differences in the way dermally applied cyclohexane is handled by the two sexes.

 

Less than 0.1% of the dose remained in the carcass 72 h after dermal exposure to cyclohexane at 100 mg/cm² and less than 0.4% of the dose remained in the carcass 72 h after dermal exposure to cyclohexane at 1 mg/cm². Thus, neither cyclohexane nor its metabolites would be expected to accumulate after repeated exposure to cyclohexane.

Applicant's summary and conclusion

Conclusions:

Cyclohexane is rapidly excreted. Expired air is the major route of excretion, urinary excretion also occurs with essentially no radioactivity in faeces. Approximately 39 and 60% of a dermal dose of 1mg/cm2 cyclohexane (primarily vapour) were absorbed in male and female rats respectively; the corresponding value after a dermal dose of 100mg/cm2 (primarily liquid) was 4% for both sexes. AUC(0-∞) values for radioactivity in blood indicate a sex difference in systemic exposure following dermal exposure to cyclohexane.