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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, non-guideline human experimental study, published in peer reviewed literature, limitations in design but adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Dermal, oral and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human volunteers
Author:
Prah J, Ashley D, Blount B, Case M, Leavens T, Pleil J, Cardinali F
Year:
2004
Bibliographic source:
Toxicological Sciences 77, 195-205

Materials and methods

Principles of method if other than guideline:
Fourteen human volunteers were dermally exposed by placing one arm in a tank with a solution of MTBE in water for 1 hour. Blood and exhaled breath samples were obtained throughout and after the exposure period and analysed for MTBE and TBA (tert butyl alcohol). The dermal permeability coefficient was calculated.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
human
Sex:
male
Details on test animals and environmental conditions:
Upon arrival at the laboratory, the volunteers were examined for continued good health and gave urine samples. The subjects were asked to avoid exposure to gasoline before or after the study. The skin of the exposed arms in the dermal study was intact with no obvious defects that would enhance or impair the penetration of the test substance. An intravenous catheter was inserted into an antecubital vein and baseline blood sample was obtained.

Administration / exposure

Vehicle:
water
Duration of exposure:
1 hr
Doses:
52.05 (+/- 0.212) ug/ml in water
No. of animals per group:
14 human volunteers
Control animals:
no
Details on study design:
Dermal exposure
The exposure system consisted of a glass pipe with a total volume of 11.12 L that was mounted in an insulated plywood box. During exposure, the system was mounted on a modified body plethysmograph. The body plethysmograph was altered to add charcoal-filtered air flowing to minimize the inhalation exposure to MTBE insertion or removal of the arm. The subject inserted his arm through the sleeve, and a medical tourniquet was gently applied to the upper arm to provide a leak-proof fit. The tank was filled with tap water at 41–43°C and MTBE was added to obtain a final concentration of 81 ul/L. The contents were stirred with a disposable glass rod. A sample was obtained for MTBE analysis 2 min after mixing.
At the end of the exposure the subject withdrew his arm, which then was toweled dry. Water samples and temperature measurements were obtained at baseline and 5, 30, and 65 min after the start of exposure.

Sample collection and analysis
Blood samples were collected at 5, 15, 30, 45, 60, 75, 90, 120, 180, 240, 360 and 1440 minutes after the start of exposure. Exhaled breath samples were obtained simultaneously with the blood samples. MTBE and TBA were measured in blood by gas chromatography/mass spectroscopy (GCMS) after extraction by a purge and trap technique. Breath samples were also analyzed by GCMS and samples were normalized based on CO2 levels.

Calculation of dermal absorption
The dermal permeation coefficient was calculated by using the formula P = M/ACt in which P is the permeation coefficient, M is the MTBE in the body, A is the area exposed, C is the aqueous concentration, and t is the exposure duration in hours (McDougal, 1998). The surface area for each subject’s arm and hand was determined by multiplying the subject’s body surface area by 0.078, the fraction of the surface area of the arm and hand of a 70 kg. Body surface was determined for each subject using a nomogram.

Reference
McDougal, J. N. (1998).Prediction-physiological models. In Dermal Absorption and Toxicity Assessment (M. S. Roberts and K. A. Walters, Eds.). Marcel Dekker, New York, NY.

Results and discussion

Percutaneous absorption
Parameter:
percentage
Absorption:
ca. 0.2 %
Remarks on result:
other: Permeability coefficient (Kp) = 0.0035 cm/hour (at a realistic temperature of 32 °C)

Any other information on results incl. tables

A permeability coefficient of MTBE of 0.028 cm/hour at a skin temperature of 38.5 °C was measured.

Temperature correction

The temperature chosen in the experiment was not realistic for the actual situation since the skin of hands is about 25.4 °C and of the lower arms about 30.3 °C (at an ambient temperature of 25 °C) (Cross et al. 2008). As such, skin permeation coefficients measuredin vitroare determined at 32 °C (OECD TG 428 “skin Absorption: in vitro method”).

Because skinpermeation coefficients are strongly temperature dependent (Gordon et al. 1998), a correction for temperature is needed to extrapolate the coefficient measured by Prah et al. to an actual situation. In a study of Gordon et al. (1998), the effect of water temperature on skin penetration of chloroform was studied. The difference between the permeation coefficient at 38 °C and 32 °C was estimated to be about an order of magnitude of 8 (Gordon et al. 1998).

 

Correcting the skin permeation coefficient of MTBE (measured at 38.5 °C) for temperature according to the results found in the study of Gordon, results in a corrected permeation coefficient of 0.028/8 = 0.0035 cm/hour (at a realistic temperature of 32 °C).

For the calculation of the percentage dermal absorption, an aqueous Kp of 0.004 cm/hour was used (which is more worse-case)

Derivation of initial absorption

As is deduced in EHC 235 (2006), the following equation is true:

 Kp= Kmx D/h                                                                         [1]                             

(Kp is the permeability coefficient; Km is the pseudo-homogeneous partition, or distribution coefficient between the stratum corneum and the vehicle; D is the effective diffusion coefficient; h is the membrane thickness)

 

To derive the Kp for the neat substance, the aqueous Kp has to be divided by the stratum corneum/water partition coefficient (Km). The Km (stratum corneum/water) for MTBE was calculated to be 2.06 by using the QSAR described by Ten Berge (2009).

Since the aqueous Kp was 0.004 cm/hour, the Kp for neat liquid is: 0.004 / 2.06 = 0.00194 cm/hour.

 

To derive the initial absorption of neat MTBE, the Kp for neat liquid has to be multiplied by the density. The density of MTBE is 741 mg/cm3.

Therefore the initial absorption of neat MTBE is 0.00194 cm/hour x 741 mg/cm3= 1.44 mg/cm2/hour

 

The above mentioned explanation can alternatively be expressed as follows:

Initial absorption (mg/cm2/hr) = rholiquid* (D/h)                           [2]

(rholiquid is the density of the liquid (mg/m3); D is the diffusion coefficient of the liquid in the stratum corneum (cm2/hr); h is the tickness of the stratum corneum)

 

D/h = Kp/Km                                                                                          [3]

(Kp is the permeability coefficient; Km is the stratum corneum/water partition coefficient)

 

Substitution of equation 3 in 2 gives:

Initial absorption (mg/cm2/hr) = rholiquid* Kp/Km                                           [4]

 

The density of MTBE is741 mg/cm3; the Kpand Kmwere determined to be 0.004 cm/hour and 2.06, respectively.

As such, the initial absorption (mg/cm2/hr) = 741 * 0.004/2.06 = 1.44 mg/cm2/hour

 

In conclusion, the initial absorption of neat MTBE is 1.44 mg/cm2/hour.

 

Correction for evaporation

Since MTBE is very volatile, a strong competition between evaporation and skin absorption will occur in case the skin is exposed to neat MTBE.

Based on the REACH Guidance appendix R14.1, it was calculated that the evaporation rate of MTBE is 1008 mg/cm2/hour.

Therefore, of each dose of MTBE exposed to the skin 0.143% (1.44/1008) is available for skin absorption because of the majority of the MTBE evaporates before absorption can occur.

As such, the percentage of dermal absorption of MTBE is assumed considered to be 0.143%. For the calculation of the dermal DNEL, a percentage of dermal absorption of 0.2% is used (to be at the safe site).

 

In conclusion, the percentage of dermal absorption of MTBE is 0.2%. This value is used for the calculation of the DNEL for dermal exposure.

References

Cross A, Collard M, Nelson A, 2008. Body Segment Differences in Surface Area, Skin Temperature and 3D Displacement and the Estimation of Heat Balance during Locomotion in Hominins. PLosONE 3(6),1-9 [e:2464].

 

EHC 235 Environmental Health Criteria 235: Dermal Absorption, World Health Organization 2006.

 

Gordon SM, Wallace LA, Callahan PJ, Kenny DV, Brinkman MC, 1998. Effect of Water Temperature on Dermal Exposure to Chloroform Environ Health Perspect 106, 337-345.

 

Prah J, Ashley D, Blount B, Case M, Leavens T, Pleil J, Cardinali F, 2004. Dermal, Oral, and Inhalation Pharmacokinetics of Methyl Tertiary Butyl Ether (MTBE) in Human Volunteers. Toxicological Sciences 77, 195–205.

 

OECD TG 428 “skin Absorption: in vitro method”

 

ten Berge W, 2009. A simple dermal absorption model: derivation and application. Chemosphere 75(11), 1440-5.

Applicant's summary and conclusion