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Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Reliable without restriction; the study was conducted according to GLPs and is in compliance with the Environmental Protection Agency final rule (40 CFR Parts 9 and 799).
Objective of study:
absorption
Qualifier:
according to
Guideline:
other: The study is in compliance with the Environmental Protection Agency final rule (40 CFR Parts 9 and 799), In Vitro Dermal Absorption Rate Testing of Certain Chemicals of Interest to the Occupational Safety and Health Administration.
Deviations:
yes
Remarks:
Two minor protocol deviations were reported, neither of which had an adverse impact on any of the study data.
Principles of method if other than guideline:
The study evaluated the rate and amount of [^14C]-methyl isoamyl ketone absorbed across human skin after in vitro exposure, and evaluated the disposition of [^14C]-methyl isoamyl ketone in the various layers (stratum corneum, epidermis, and dermis) of human skin after in vitro exposure.

Human skin samples were incubated for 10 minutes or 1 hour with the epidermal surface exposed to [^14C]-methyl isoamyl ketone in a Bronaugh flow-through diffusion cell under occluded conditions. The amount of [^14C]-methyl isoamyl ketone absorbed across the skin into the receptor fluid and the disposition of [^14C]-methyl isoamyl ketone in the various skin layers following each incubation period was determined by liquid scintillation counting. Receptor fluid collected at 10 minutes and 1 hour was used to calculate the rate and amount of absorption.
GLP compliance:
yes
Radiolabelling:
yes
Species:
human
Sex:
male/female
Details on test animals and environmental conditions:
Skin was obtained from the abdominal region of human cadavers via an organ procurement agency.
Route of administration:
other: in vitro, dermatomed skin
Vehicle:
unchanged (no vehicle)
Details on exposure:
Tissue Incubation:
Two sets of skin disks were dosed with [^14C]-methyl isoamyl ketone dosing solution. Each set contained two skin disks from each donor for a total of six skin disks per incubation set. Skin disks with acceptable barrier function were dosed with 200 μL of the [^14C]-methyl isoamyl ketone dosing solution on the epidermal surface of each disk. The skin disks were incubated for 10 minutes or 1 hour under occluded conditions and the receptor fluid was collected as specified below.

Set 1: The skin disks were incubated for 10 minutes and the receptor fluid was collected at 10 minutes.

Set 2: The skin disks were incubated for 1 hour and the receptor fluid was collected at 1 hour.

At the end of the incubation period for each set, the skin surface was wiped with cotton swabs, washed twice with detergent and twice with water. After the last wash, the skin disks were removed from the diffusion cells and separated into component layers (stratum corneum, epidermis, and dermis). Each skin layer was digested in 1 mL of 1 N sodium hydroxide and retained for liquid scintillation counting. The sides of each diffusion chamber were also wiped with cotton swabs to obtain any [^14C]-methyl isoamyl ketone remaining in the diffusion chamber after each skin disk had been removed.
Duration and frequency of treatment / exposure:
Once for either 10 or 60 minutes.
Remarks:
Doses / Concentrations:
20.2 μCi/mL (1 donor) and 20.3 μCi/mL (2 donors).
Details on study design:
Tissue Preparation:
Skin samples were obtained from the abdominal region of five human cadavers obtained through an organ procurement agency and were stored at –20°C prior to use. The skin was processed to remove the subcutaneous fat layer and cut with a dermatome (Padgett Dermatome, Model B, S/N 1-8314) to a split thickness of 290-400 μm. Skin disks were prepared from the dermatomed skin and used for the incubations on the same day. The disks were prepared using a cork-boring tool and stored in receptor fluid kept on wet ice until incubation. Five skin disks (16–20 mm in diameter) per donor were used for the incubations.

Receptor Fluid:
The receptor fluid flowing across the lower surface of the skin was Hanks’ balanced salt solution (Gibco, lot 1327456) containing 6% polyethoxyoleate (Sigma, lot 069H0140) and antibiotics (TorpedoTM Antibiotic Mix, In Vitro Technologies, lot C13046C). The pH of the receptor fluid was 7.40-7.45.

Analysis:
Cotton swabs used to remove [^14C]-methyl isoamyl ketone from the skin surface or the sides of the diffusion chamber, and cotton swabs used in the washes were extracted with liquid scintillation cocktail. Liquid scintillation cocktail was added to the entire volume or an aliquot of each of the fractions (skin layer digests or receptor fluid collections). The extracted swab samples and the fractions mixed with liquid scintillation cocktail were placed in the dark at ambient temperature for at least 24 hours to allow chemiluminescence to decay and analyzed using a liquid scintillation counter (Beckman, Model LS5000TA, Serial No. 7040864).

Criteria for Data Acceptance:
Data were accepted since the data were obtained using skin disks with sufficient barrier function. Prior to the determination of the percutaneous absorption of methyl isoamyl ketone, the permeability of tritiated water was determined in all the human skin disks. All skin disks used in the experiments had to have tritiated water absorption within the limits of acceptance, or < 0.3% penetration following incubation of up to one hour.
Statistics:
The amount of [^14C]-methyl isoamyl ketone absorbed across the skin barrier was calculated and expressed as μg/hour/cm^2. The percent distribution of [^14C]-methyl isoamyl ketone in each of the skin layers was determined. The mass balance of the test substance was also calculated. All calculations, including mean and standard deviation values, were performed using Microsoft® Office Excel 2000.

Percutaneous absorption of methyl isoamyl ketone:

The average absorption of methyl isoamyl ketone into the receptor fluid following 10-minute exposure was 0.683 ± 1.07 μg/cm^2; thus, the first short-term absorption rate was 4.10 ±6.42 μg/cm^2/hour. The average absorption of methyl isoamyl ketone into the receptor fluid following 1-hour exposure was 37.4 ± 65.2 μg/cm^2; thus the second short-term absorption rate was 37.4 ± 65.2 μg/cm^2/hour.

Cutaneous disposition of methyl isoamyl ketone:

Data are summarized in tables 1 and 2.

-The average amount of MIAK present in the stratum corneum was 67.6 ± 130 and 4.35 ± 3.85 μg/cm2 following exposure for 10 minutes and 1 hour, respectively.

-The average amount of MIAK present in the epidermis was 6.14 ± 7.72 and 3.38 ± 1.93 μg/cm2 following exposure for 10 minutes and 1 hour, respectively.

-The average amount of MIAK present in the dermis was 24.5 ± 22.7 and 12.3 ± 6.14 μg/cm2 following exposure for 10 minutes and 1 hour, respectively.

-The average amount of MIAK present in the water used for heat separation of epidermis and dermis was 36.6 ± 17.0 and 32.7 ± 35.0 μg/cm2 following exposure for 10 minutes and 1 hour, respectively.

Total absorbed and recovered methyl isoamyl ketone:

The total absorbed amount of methyl isoamyl ketone was estimated based on the amount of [^14C]-methyl isoamyl ketone in the stratum corneum, epidermis, dermis, the water used to separate dermis and epidermis, and the receptor fluid. The total amount of methyl isoamyl ketone absorbed was 135 ± 135 and 90.2 ± 107 μg/cm², following exposure for 10 minutes and 1 hour, respectively. This corresponded to 0.0529 ± 0.0527 and 0.0352 ± 0.0420% of the total applied dose, following exposure for 10 minutes and 1 hour, respectively.

The total amount of MIAK recovered from the incubations (mass balance) was estimated based on the amount in all the surface wash fractions, the various skin layers, the water used to separate dermis and epidermis, and the receptor fluid. The total recovery of MIAK was 90.9 ± 2.37 and 91.7 ± 3.47% of the total applied dose following exposure for 10 minutes and 1 hour, respectively.

Conclusions:
Interpretation of results (migrated information): other: The amount of MIAK dosed onto skin disks appeared to simulate an infinite dose under study conditions. This was inferred based on observing that the total amount absorbed was considerably less than 1% of available material after 10 min or 1 hr of exposure
In this study, human skin disks were exposed in vitro to a simulated infinite dose of methyl isoamyl ketone. The total amount of MIAK absorbed was less than 1% after both 10 minute and one hour exposures.
Executive summary:

In a study designed to determine the in vitro absorption of MIAK by human skin disks after a single topical application of [^14C]- methyl isoamyl ketone, less than 1% was absorbed after both 10 minute and one hour exposures. Of the material absorbed, the majority was located in the stratum corneum after a 10-min exposure and in the dermis after a 1-hr exposure.  In this study, [^14C]- methyl isoamyl ketone was applied at a dose concentration of 20.2-20.3 μCi/mL to 6 tissue samples (two tissue samples per individual) for either 10 minutes or 1 hour, after which time radioactivity was measured in the skin layers and the surrounding receptor fluid. The short-term absorption rates for methyl isoamyl ketone were estimated to be 4.10 ± 6.42 μg/cm^2/hour (following 10-minute exposure) and 37.4 ± 65.2 μg/cm^2/hour (following 1-hour exposure). The total amount of methyl isoamyl ketone absorbed was determined to be 135 ± 135 and 90.2 ± 107 μg/cm^2, following exposure for 10 minutes and 1 hour, respectively. The amount absorbed and the amount recovered from the wash fractions accounted for 90.8 ± 2.37 and 91.7 ± 3.45% of the total applied dose following exposure for 10 minutes and 1 hour, respectively.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
32 hours
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable with restriction. Study was conducted according to generally accepted scientific principles. While there is no indication it was run in accordance with GLPs, the data have been published in a peer-reviewed journal.
Objective of study:
absorption
other: elimination from blood
Qualifier:
no guideline followed
Deviations:
not applicable
Principles of method if other than guideline:
Groups of rats received a single dose of MIAK by oral gavage or were exposed to MIAK for a single 6-hr inhalation exposure. To determine the elimination of MIAK from blood, blood was collected over a 32-hour period and analyzed quantitatively for MIAK via gas chromatography.
GLP compliance:
no
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
-Strain: CRL:COBS® CD® (SD) BR
-Source of test animals: Charles River Breeding Laboratories, Wilmington, MA
-Weight at study start: 178.0 ± 6.0 g
-Quarantine period: 10 days
-Housing: Singly in stainless steel wire-mesh cages prior to treatment
-Feed: Purina Rodent 5001 Chow, pelleted; ad libitum prior to the first blood sample
-Water: ad libitum
Route of administration:
other: Two groups of rats were exposed by oral gavage; two groups were exposed via inhalation.
Vehicle:
other: Rats dosed by gavage received undiluted methyl isoamyl ketone. For rats exposed via inhalation, MIAK was mixed with fresh air to achieve the desired exposure concentration.
Details on exposure:
Two groups of three male rats each received a single oral dose of 916 or 1830 mg/kg bw of undiluted methyl isoamyl ketone. Two groups of three male rats each received a single 6-hr vapor exposure of 930 or 1950 ppm MIAK. This study was part of a 2-week and 90-day inhalation study and the vapors for the absorption/elimination study were generated using the same methods. A MIRAN IA infrared gas analyzer monitored chamber concentrations. The 2-week and 90-day studies and details on vapor generation can be found in the Repeated Dose Toxicity section of this submission.
Duration and frequency of treatment / exposure:
Each animal received a single dose by oral gavage or a single 6-hr exposure via inhalation.
Remarks:
Doses / Concentrations:
Animals received a single oral dose of 916 or 1830 mg/kg bw or a single 6-hr inhalation exposure to 930 or 1950 ppm methyl isoamyl ketone.
No. of animals per sex per dose:
3 males/ treatment group
Control animals:
no
Details on study design:
Two groups of three male rats each received a single oral dose of 916 or 1830 mg/kg bw of undiluted methyl isoamyl ketone. Two groups of three male rats each received a single 6-hr vapor exposure of 930 or 1950 ppm MIAK. To determine the elimination of MIAK from blood, blood was collected over a 32-hour period and analyzed quantitatively for MIAK via gas chromatography.
Details on dosing and sampling:
Rats receiving a single 6-hr inhalation exposure were restrained for tail bleeding by placing them in a stainless steel mesh cylinder sealed at one end. The open end of the restrainer was mounted flush against the inside of the face plate of a 20L glass bell jar inhalation chamber. The rats’ tails protruded through small holes in the face plate to facilitate sample collection during the exposure. Rats dosed by gavage were placed in restrainers only during the tail bleeding process. The initial tail blood sample (0 hr) was obtained by clipping the end of the tail and collecting 0.1 mL of blood in a heparinized micro-Folin pipette. Subsequent blood samples were obtained by massaging the tail. The heparinized blood was transferred to a cuvette containing 0.2 mL of distilled water and capped. Blood samples were collected at 1, 2, 4 and 6-hr intervals during inhalation exposure and 1, 2, 4, 8, 10, 16, 26, and 32-hr intervals post-exposure or until blood MIAK was no longer detected. Blood from rats dosed by gavage was collected at 1, 2, 4, 6, 7, 8, 10, 14, 16, 22 and 32-hr post-gavage.
Conclusions:
Following administration of a single oral dose of 1830 mg/kg bw or a 6-hr inhalation exposure to 1950 ppm, the rate of uptake, peak concentration, and total area under the curve were roughly similar. A marked difference, however, was seen in the rate of clearance of MIAK between the two routes of administration. It is uncertain why clearance following oral administration is slower than that following inhalation exposure. However, absorption, metabolism and distribution of MIAK may differ when comparable doses of MIAK are administered either as a bolus dose to non-fasted rats by gavage, or over a 6-hr period during inhalation exposure. The prolonged clearance following oral administration in this study may be responsible, in part, for the increased liver toxicity that has been seen following oral administration.
Executive summary:

In a study to try to explain the differences in target organ toxicity observed in rats exposed repeatedly to MIAK by the oral and inhalation routes over a 13-week period, groups of rats received either a single oral dose of MIAK or a comparable 6-hr exposure to MIAK by whole body inhalation. Two groups of three male rats each received a single oral dose of 916 or 1830 mg/kg bw of undiluted methyl isoamyl ketone. Two groups of three male rats each received a single 6-hr vapor exposure of 930 or 1950 ppm MIAK. To determine the elimination of MIAK from blood, blood was collected over a 32-hour period and analyzed quantitatively for MIAK via gas chromatography. When MIAK blood values for the high oral dose were compared to blood values for the high inhalation exposure, the rate of uptake, peak concentration, and total area under the curve were roughly similar. However, there was a marked difference in the rate of clearance of MIAK between the two routes of administration. Prolonged clearance following oral administration may explain the more significant liver toxicity observed in the 90-day repeated oral exposure study compared to the 90-day repeated inhalation study, even though the administered doses were comparable.

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Reliable without restriction; the study was conducted according to GLPs and OECD Guideline 428.
Qualifier:
according to
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Deviations:
no
GLP compliance:
yes
Radiolabelling:
no
Species:
human
Sex:
not specified
Details on test animals and environmental conditions:
Dermatomed sections of human cadaver skin were obtained from the National Disease Research Interchange, Philadelphia, PA. Sufficient medical history for each donor was obtained to ensure that the tissue had not been adversely affected by any clinical condition or disease that would alter the results of this study. Samples of dermatomed skin were stored frozen at -70°C.
Type of coverage:
other: Not strictly occlusive, but the donor chamber was filled with fluid (^3H20 or MIAK), so the tissue was completely covered during the study.
Vehicle:
unchanged (no vehicle)
Duration of exposure:
6 hours for determination of the permeability of ^3H20 and 7 hours for the permeability of MIAK
Doses:
300µl
No. of animals per group:
3 different human donors were used
Control animals:
yes
Remarks:
One of the three skin samples from each donor was used as a control, i.e., was not exposed to MIAK.
Details on study design:
Overall Study Design:
The study consisted of a three-phase experiment; phases 1 and 3 were used to determine the permeability of ^3H20 and phase 2 was used to determine the permeability of the test substance, MIAK.

Tissue Samples and Sample Preparation:
Skin samples from three different human donors were used; the experiment used nine diffusion cells containing three skin preparations originating from each of the three human donors. Skin samples were collected using a dermatome at a specified thickness of 200-500µm. Each skin specimen was placed with the external surface uppermost over the opening of the receptor chamber of a diffusion cell. A CAPFE™ O-ring was placed under the skin specimen, and the donor chamber clamped in place to secure the tissue.

Receptor Solution:
The receptor solution was Dulbecco’s phosphate buffered saline containing penicillin (100 units/ml), streptomycin (100 µg/ml) and amphotericin B as Fungizone™ (0.25 µg/ml).

During each phase of the experiment, the receptor chambers were filled with the buffered (pH 7.1) isotonic saline antibiotic-antimycotic solution, and stirred continuously with a stir bar throughout the study. Duplicate background (0 hour) samples were taken from the receptor chamber of each cell. 300 µl of ^3H20 (specific activity 4.34 µCi/gram) donor solution was applied to the donor chambers for phases 1 and 3, while 300 µL of the neat test substance was applied directly to the surface of two skin samples from each donor in phase 2. The remaining skin sample was exposed to only saline during phase 2. The diffusion cells were incubated at 30°C for 6 hours in phases 1 and 3 and for 7 hours in phase 2. At hourly intervals, samples were removed from the receptor chambers in all phases and at 0, 3, 6, and 7 hours from the cells designated as the saline control of phase 2. The test substance in the receptor solution in phase 2 was assayed by GC/FID. Phase 1 and 3 solutions were assayed by liquid scintillation spectrometry (LSS; Wallac Model 1409 liquid scintillation spectrometer and polyfluor liquid scintillant). The receptor chambers were refilled after each sampling.

After the first two phases, the donor and receptor chambers were emptied, rinsed three times with saline, and refilled with antibiotic-antimycotic saline. The cells were allowed to stir overnight, after which they were emptied, rinsed, and refilled with the receptor solution for phase 3. The rate of increase in the concentration of the test substance or ^3H2O in the receptor chamber of each cell was used to calculate a permeability constant (cm/hr) and an absorption rate (mg/cm^2/hr) for the test substance and ^3H2O.
Details on in vitro test system (if applicable):
Each skin specimen was placed with the external surface uppermost over the opening of the receptor chamber of a Franz-type diffusion cell. A CAPFE™ O-ring was placed under the skin specimen, and the donor chamber clamped in place to secure the tissue.
Dose:
Phase 1: ^3H2O 300 µl
Remarks on result:
other: Absorption (%) (upper value): 2.12 ± 1.01 mg/cm^2/hr. Although slightly higher, this value was comparable to the historical control (n=27) of 1.62 ± 0.89 mg/cm^2/hr.
Dose:
Phase 2: MIAK 300 µl
Remarks on result:
other: Absorption (%) (upper value): 0.21 ± 0.15 mg/cm^2/hr. Permeability constant for study: 2.61X10^-4 cm/hr. 6 skin specimens exposed to test substance; remaining 3 specimens exposed to physiological saline served as controls for damage ratio calculations.
Dose:
Phase 3: ^3H2O 300 µl
Remarks on result:
other: Absorption (%) (upper value): 2.35 ± 1.22 mg/cm2/hr. Although slightly higher, this value was comparable to the historical control (n=27) of 1.62 ± 0.89 mg/cm^2/hr.

The mean damage ratio for phase 2 was 1.02 ± 0.14 and 1.10 ± 0.12 for phase 3. The value in phase 2 was within the range of damage ratios presented by Dugard et al (1984) of 1-2 for water and within acceptable ranges of the testing facility. Exposure to the test substance for 7 hours produced similar damage ratios to those expected from exposure to physiological saline. 

If it is assumed that skin absorption in man is similar to that of this in vitro study, then the internal dose of MIAK from a 1 hour exposure would be 2.19 mg/kg if the area of the hands is approximately 720 cm^2 in an average adult (70 kg).

Conclusions:
In an in vitro dermal absorption study, the mean absorption rate of methyl isoamyl ketone through dermatomed human skin specimens was 0.21 ± 0.15 mg/cm^2/hr with a corresponding permeability constant of (2.61 ± 1.81) x 10^-4 cm/hr. Based on criteria established by Marzulli et al. (1969), the test substance would be considered a “moderate” penetrant relative to other chemical species. These data can be used to estimate the uptake in man following dermal exposure assuming that skin absorption in vivo is similar to that measured in vitro. Assuming an adult weighs 70 kg, the internal dose from a 1-hr exposure to both hands would be 2.19 mg/kg. The mean damage ratio for this study was not different from that expected from exposure to physiological saline. It is concluded that, under the conditions used in this study, methyl isoamyl ketone did not cause significant damage to the skin and that MIAK is absorbed through the skin.
Executive summary:

In an in vitro dermal absorption study, methyl isoamyl ketone was applied to dermatomed skin specimens using a Franz-type diffusion cell and incubated for 7 hours at 30°C. The receptor chambers were filled with buffered isotonic saline containing an antibiotic-antimycotic solution, and stirred continuously with a stir bar throughout the study. 300 µl of ^3H20 (specific activity 4.34 µCi/gram) donor solution was applied in the donor chambers in two separate experiments (phases 1 and 3) and 300 µL of the neat test substance was applied directly to the surface of the skin in a separate phase (phase 2).  At hourly intervals, samples were removed from the receptor chambers and the test substance in the receptor solution was assayed by GC/FID. ^3H20 was assayed by liquid scintillation spectrometry. The mean absorption rate of methyl isoamyl ketone was 0.21 ± 0.15 mg/cm^2/hr with a permeability constant of 2.61X10^-4 cm/hr. The mean damage ratio was 1.02 ± 0.14, which was within the range of damage ratios presented in the published literature and the testing facility. It was concluded that exposure to methyl isoamyl ketone for 7 hours produced damage similar to that observed with physiological saline. Using the definitions suggested by Marzulli, Brown and Maibach (1969), MIAK would be classified as moderate with respect to its absorption through human skin.

Description of key information

Key value for chemical safety assessment

Additional information

The absorption and elimination of methyl isoamyl ketone from blood and in urine is well understood. In a study designed to try to explain the difference in severity of target organ toxicity observed in rats exposed repeatedly to methyl isoamyl ketone by the oral and inhalation routes over a 13-week period, groups of rats received either a single oral dose of MIAK or a comparable 6-hr exposure to MIAK by whole body inhalation. Two groups of rats received either a single oral dose of 916 or 1830 mg/kg bw of undiluted test material by oral gavage while two groups of rats received a single 6-hr vapor exposure of either 930 or 1950 ppm MIAK. To determine the elimination of MIAK from blood, blood samples were collected over a 32-hr period and analyzed quantitatively for MIAK via gas chromatography. When MIAK blood values for the high oral dose were compared to blood values for the high inhalation exposure, the rate of uptake, peak concentration, and total area under the curve were roughly similar but there was a marked difference in the rate of clearance between the two routes of administration. Elimination rates following a 6-hr inhalation exposure to either 930 or 1950 ppm MIAK were similar (T1/2 < 1 hr) while elimination rates of MIAK from blood appeared to be more rapid at the lower level (T1/2 = 2.1 hr) versus the higher dose level (T1/2 = 5.2 hr) following oral administration. This suggests that elimination of MIAK may saturate at higher oral doses. Prolonged clearance following oral administration may explain the more significant liver toxicity following a 90-day repeated oral exposure compared to that observed for a 90-day inhalation exposure, even though administered doses were comparable. 

To compare the excretion pattern of MIAK following administration by the dermal and intravenous routes, groups of 3 or 4 Beagle dogs received a single dose of radiolabeled MIAK and urine voidings were collected for 8 hours. Dermal absorption of methyl isoamyl ketone was estimated to be 35-90 mg for a 20-60 minute exposure. There was no direct correlation observed between the duration of skin contact and the quantity of MIAK absorbed. Rats dosed repeatedly with MIAK showed increased liver weights, effects usually seen with the induction of drug metabolizing enzymes. The variability seen in the MIAK results may be related to metabolic factors that affect its elimination by the dog. Dogs dosed intravenously with [2-14C] MIAK eliminated about 12.3% of the dose in eight hours. 

In an in vitro dermal absorption study, the mean absorption rate of methyl isoamyl ketone through dermatomed human skin was 0.21 ± 0.15 mg/cm^2/hr with a corresponding permeability constant of (2.61 ± 1.81) x 10^-4 cm/hr. The mean damage ratio for this study was not different from that expected from exposure to physiological saline. Based on criteria established by Marzulli et al. (1969) MIAK is considered to have a moderate potential for absorption compared to other chemical species. In a second in vitro dermal absorption study, human skin samples were incubated for 10 minutes or 1 hour with the epidermal surface exposed to radiolabeled MIAK. The total amount of MIAK absorbed through to the receptor solution was less than 1% after both 10 minute and one hour exposures. Of the material absorbed, the majority was located in the stratum corneum after a ten minute exposure while a higher percentage was in the dermis following a one hour exposure.