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Endpoint:
dermal absorption
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Study period:
2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
Prediction is based on QSAR calculations of JMax and the use of a test set of similar compounds. It should be noted that dermal absorption predictions are often reported to be + or- 30%.
Justification for type of information:
Percent absorption of a chemical is dependent upon a variety of factors including the dose concentration of the test solution. Because absorption is not always linear and reaches a maximum, a percent absorption calculated from one study may not be fully relevant for another study. Percent dermal absorption data were not available for 1-Butanol, 3-methoxy-3-methyl (CAS# 56539-66-3). Therefore, a combination of QSAR and read-across were implemented to estimate the % dermal absorption for this molecule.
Principles of method if other than guideline:
EPISUITE DERMWIN
QSAR calculation of Jmax
Details on study design:
Reference for predictions of the maximum solute flux is attached.
Absorption in different matrices:
A maximum solute flux (Jmax) of 0.085 mg/cm2/hr was predicted from the QSAR developed by Magnusson et al. (2004). A percent absorption of 42% was estimated based on read-across to similar compounds.
Conversion factor human vs. animal skin:
no conversion required. The QSAR was developed using data collected on the flux of solutes across human skin.

Percent absorption of a chemical is dependent upon a variety of factors including the dose concentration of the test solution. Because absorption is not always linear and reaches a maximum, a percent absorption calculated from one study may not be fully relevant for another study. Percent dermal absorption data were not available for 1-Butanol, 3-methoxy-3-methyl (CAS# 56539-66-3). Therefore, a combination of QSAR and read-across were implemented to estimate the % dermal absorption for this molecule. 

 

Maximum dermal absorption (Jmax) was predicted using a QSAR developed by Magnusson et al (2004). The QSAR was developed based on flux data through human skin for 84 molecules. The 278 molecules in the training set includes some that were structurally similar to 1-Butanol, 3-methoxy-3-methyl. The log Kow and molecular weight of MMB were within the domain of the training set molecules. Jmax of MMB was predicted to be 0.085 mg/cm2/hr. The Magnusson et al (2004) manuscript and Table S1 with the training set molecules and data are attached.

 

Read-across was then used to relate this value to measured % dermal absorption values for similar molecules. The molecules were obtain via a similarity search from the Chemspider website with the search parameter set to >85% similarity. EPIWIN was used to calculate the physical chemical properties for the read-across molecules. In addition to being structurally similar, MMB fits within the bounds of the molecular weight, log Kow, and solubility for these molecules. Therefore, they are considered to be valid molecules for read across. Dermwin was then run in batch mode to calculate the Derwin Dermal Penetration Event for the molecules. In batch mode, Dermwin utilizes the log Kow calculated solubility for the molecule and an event duration of 0.58 hrs. Because the EPIWIN and DERMWIN were run in batch mode with no alterations further documentation on these models is not provided herein.

Table of Chemicals Used for Read Across. Registration chemical is highlighted in Green.

Conclusions:
A calculation using the EPIDERM model resulted in a maximum solute flux (Jmax) of 0.085 mg/cm2/h of MMB through human skin.
Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-12-04 to 2013-01-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Qualifier:
according to
Guideline:
other: - OECD Environmental Health and Safety Publications, Series on Testing and Assessment no. 28. Guidance document for the conduct of skin absorption studies (March 2004).
Qualifier:
according to
Guideline:
other: - OECD Guidance Notes on Dermal absorption, Draft 22 October 2010
Qualifier:
according to
Guideline:
other: - European Commission Guidance Document on Dermal Absorption – Sanco/222/2000/Rev. 7 (19 March 2004)
GLP compliance:
yes (incl. certificate)
Radiolabelling:
yes
Species:
human
Strain:
not specified
Sex:
not specified
Type of coverage:
occlusive
Vehicle:
water
Duration of exposure:
24 h
Doses:
undiluted (100%) mixed with 3-Methyl-3-methoxy[4-14C]butan-1-ol
aqueous dilution (10%) mixed with 3-Methyl-3-methoxy[4-14C]butan-1-ol
Details on study design:
Human skin was placed into flow-through cells and exposed to 3-Methoxy-3-methyl-1-butanol for 24 hours under occlusion conditions. The receptor fluid was collected at various time points. At the end of the experiments the amount of radioactivity was determined at the donor site, in the skin (tape-stripping and total skin) and in the receptor fluid. Prior to the determination of the dermal absorption of 3-Methoxy-3-methyl-1-butanol, the skin integrity was checked by determination of the permeation of tritiated water.

- Justification of species, anatomical site and preparative technique: Human skin is a recommended test system forin vitroskin absorption studies.
Details on in vitro test system (if applicable):
- Flow-through system: The skin penetration study was performed on a flow-through cell system consisting of :
peristaltic pump; 13 flow-through cells, diameter 9 mm (Permegear, Bethlehem, PA, USA), fraction collector and thermostat.
- Alliance HT Separations module 2795 liquid chromatograph and a
- Radio-Detector:ß-RAM Model 4 (Lablogic, Sheffield, England).
The receptor fluid was pumped at a flow rate of 1.5 mL/h.
- Test temperature: The skin surface temperature was 32±1ºC
- Humidity: ambient humidity (30-70%)
- Occlusion: yes
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Absorption in different matrices:
The receptor fluid consisted of saline (0.9% NaCl solution); donor chamber was occluded during the exposure.
A maximum solute flux of 0.055mg/cm²/h for the pure MMB and 0.113 mg/cm²/h for the 10% aqueous solution was determined.
Total recovery:
Undiluted sample (100%): 84 +- 11%
Aqueous dilution (10%) : 80 +-4%

Dose:
10%
Parameter:
percentage
Absorption:
33 %
Remarks on result:
other: 4h
Remarks:
lag time 2h
Dose:
10%
Parameter:
percentage
Absorption:
40 %
Remarks on result:
other: 24h
Remarks:
lag time 2h
Dose:
100%
Parameter:
percentage
Absorption:
4 %
Remarks on result:
other: 8h
Remarks:
lag time 2.5h
Dose:
100%
Parameter:
percentage
Absorption:
6.9 %
Remarks on result:
other: 24h
Remarks:
lag time 2.5h

Radiochemical purity:

The radiochemical purity of a stock solution of3-Methyl-3-methoxy[4-14C]butan-1-olin 0.1% TFA in MQ/Acetonitrile (1:1, v/v) was determined at the start of the study. The radiochemical purity was 98.9% and 99.3% (based on two independent injections), which was above the required 97%.

 

Homogeneity of test substance samples mixed with 3-Methyl-3-methoxy[4-14C]butan-1-ol:

The results of the homogeneity check of the formulations mixed with 3-Methyl-3-methoxy[4-14C]butan-1-olare presented inTable 2. The relative standard deviations from samples taken from the top, middle and bottom of the vial were below 3% and thus all formulations were homogeneous.

 

Table 2:  Results of homogeneity check of formulations

Formulation

Activity

(MBq/mL)

Subsample

counted

(mL)

Activity (dpm)

MBq/mL

Undiluted (100%)

2.1

0.005

T: 631078

M: 623856

B: 606871

2.104

2.080

2.023

 

 

 

Average

RSD

2.1

2.0%

 

2.0

0.010

T: 1207028

M: 1197346

B: 1203662

2.012

1.996

2.006

 

 

 

Average

RSD

2.0

0.4%

Aqueous dilution (10%)

1.9

0.005

T: 580451

M: 572013

B: 551076

1.935

1.907

1.837

 

 

 

Average

RSD

1.9

2.7 %

 

2.0

0.010

T: 1198504

M: 1213581

B: 1231184

1.998

2.023

2.052

 

 

 

Average

RSD

2.0

1.3%

RSD: relative standard deviation

Table 3:   Results of the solubility test in the receptor fluid

Formulation

Expected activity in receptor fluid

Actual activity in receptor fluid

Dose

(g/L)

Activity

(MBq/mL)

Volume formulation applied (µL)

Volume receptor fluid (mL)

Activity (kBq/mL)

Subsample counted (mL)

(DPM)

(kBq/mL)

Recovery (%)1)

0.922

2.1

6.4

36

0.368

1.0

23365

0.389

106

 

 

 

1.0

23353

0.389

106

 

 

 

1.0

23266

0.388

105

 

 

 

 

 

Average

0.389

106

 

 

 

 

SD

0.0009

 

 

 

 

 

RSD

0.23%

 

1) ratio of activity in receptor fluid solution and the activity of formulation in receptor fluid, multiplied by 100

Skin integrity:

The permeability coefficients for tritiated water for the skin discs that have been used for this study are presented inTable 4. The integrity of the reported skin discs was within the acceptability criteria (Kp< 4.5 x 10-3cm/h).

Table 4: Skin integrity values

Test substance sample

Skin disc (donor number-disc number)

Kp value for tritiated water (*10-3cm/h)

undiluted

(100%)

2796-03

2824-08

2796-04

2824-11

2825-04

2830-04

3.80

1.93

4.02

1.90

2.15

3.13

Aqueous dilution

(10%)

2825-01

2830-01

2832-05

2830-05

 

 

2.75

3.58

3.49

2.97

 

 

Table 5: Dermal absorption parameters and percentage absorption of 3-Methoxy-3-methyl-1-butanol in human skinin vitro

Formulation

Undiluted 100%

(0.922 g/mL)

Aqueous dilution 10%

(0.092 g/mL)

Skin samples

human (n=6)

human (n=4)

% RAD1)

SD2)

% RAD1)

SD2)

DERMAL ABSORPTION PARAMETERS

 

 

 

Lag time (h)

1-3

 

1-2

 

Maximum flux (µg/cm2/h)

0.055

0.018

0.113

0.020

SURFACE COMPARTMENT

 

 

 

 

Total skin swabs 24 h

0.16

0.08

0.73

0.55

Material remaining in donor chamber

77

12

39

4

Total % non-absorbed3)

78

12

40

4

SKIN COMPARTMENT

 

 

 

 

Skin

0.09

0.04

0.35

0.06

Tape strips 1&2

0.01

0.01

0.005

0.004

Stratum corneum

(tape strips excluding 1&2)

0.03

0.01

0.03

0.01

Total % at dose site

(without tape strips 1&2)

0.13

0.04

0.38

0.06

RECEPTOR COMPARTMENT

 

 

 

 

Receptor fluid (collected over 24 h)

7

2

40

1

Receptor fluid terminal

0.03

0.01

0.04

0.03

Receptor chamber

0.03

0.02

0.07

0.07

Total % directly absorbed4)

7

2

40

1

OVERALL ABSORPTION

 

 

 

 

Total % potentially absorbable

(without tape strips 1&2)5)

7

2

40

1

Total % recovery

84

11

80

4

1)RAD = radioactivity

2) SD= Standard deviation

3)Total % non-absorbed = % in total skin swabs 24 h + % material remaining in donor chamber

4)Total % directly absorbed = % receptor fluid + % receptor fluid terminal + % receptor chamber

5)Total % potentially absorbable (without tape strips 1&2) = Total % at dose site (without tape strips 1&2) + total % directly absorbed

Conclusions:
The in vitro dermal absorption of human skin with 3-Methoxy-3-methyl-1-butanol was 7 ± 2% for the undiluted substance and 40 ± 1%.for the 10% aqueous solution over a penetration time of 24 hours. A maximum solute flux of 0.055mg/cm²/h for the pure MMB and 0.113 mg/cm²/h for the 10% aqueous solution was determined.

Description of key information

The in vitro dermal absorption of 3-Methoxy-3-methyl-1-butanol through human skin was 40% for a 10% aqueous solution over a penetration time of 24 hours. Other absorption rates have been assumed as 100% as no detailed studies are available.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
40
Absorption rate - inhalation (%):
100

Additional information

One experimental toxikokinetic study is available for MMB and used in the basic assessment. Additionally validated predictions of the physiological properties of the substance itself and chemically similar substances have been considered.

Absorption:

Oral and inhalation route of exposure: Due to its water solubility and low Molecular weight MMB can be expected to be readily absorbed via oral and inhalation routes. An absorption percentage of 100 % has been taken into account for these routes.

Dermal route of exposure: MMB was tested in an in vitro skin absorption study using human skin and radiolabelled test substance following OECD 428. Two concentrations (100% and 10% MMB in water) were applied over a period of 24 hours. Rapid absorption was detected at the 10% concentration within the first four hours whereas the absorption of the undiluted sample was absorbed much slower. After 24 hours of exposure 7 ± 2% for the undiluted substance and 40 ± 1% of the 10% aqueous solution were absorbed by the receptor fluid. A maximum solute flux of 0.055mg/cm²/h for the pure MMB and 0.113 mg/cm²/h for the 10% aqueous solution was determined.

A DERMWIN QSAR calculation was done with a set of 20 similar alcohols. As a result, MMB was predicted to be absorbed through the skin in humans with a rate of 0.085 mg/cm2/hr. This result corresponds well to the experimental value of 0.055 mg/cm²/h. In addition a dermal absorption rate of 42% was predicted in the calculation compared to an experimental absorption for the pure substance of only 7%.

Taking into account that most professional and consumer applications of MMB involve aqueous solutions and take less than 24 hours, a general dermal absorption rate of 40% is considered as worst case route to route assessment factor in the DNEL calculations.

Distribution: 

The distribution of MMB is expected to occur primarily to liver and kidneys, which is in agreement with the results of repeated dose toxicity studies. Pathology of test animals has shown an increase of kidney and liver weights.

Metabolism: 

A substantial amount of the substance is expected to undergo ether-bond cleavage to the diole and methanol. The diole metabolite 3-Methyl-1,3-butandiol (CAS 2568-33-4) is a well described substance and not classified as a hazardous following CLP (SDS Sigma Aldrich, 1 -08 -2012).

3-Methyl-1,3-butandiol i

s fully water soluble and can be expected to be excreted fast. Glycoles are known to be consumed by oxidation to the aldehyde and further to the carboxylic acid. 3-Methyl-1,3-butandiol (CAS 2568-33-4) will therefore further metabolize to hydroxy isovalerianic acid (CAS 650 -08 -1). An other metabolite of MMB which may be formed by the combined reaction of ether-cleavage and oxidation is the well known substance ß-Hydroxy-ß-methylbutyric acid (HMB) (CAS 625 -08 -1). HMB is a metabolite of leucine and produced in the human body in amounts of 0.2 - 0.5 g/day.  All metabolites can be expected to be excreted via urine or enter metabolic pathways to produce CO2. No particular toxic effects are known from any of these metabolites.

Excretion: 

From toxicokinetic investigations of similar molecules such as propyleneglycol methylether (CAS 107-98-2), and dipropyleneglycole methylether (CAS 34590-94-8), it is expected that the substance is excreted mainly in the form of its sulfate-conjungate and glucuronic conjungate, but also as such due to its water solubility (OECD SIDS Report for 17 SIAM, Propylene glycol ethers, 2003). From a similar substance, 1-Butoxypropan-2-ol (CAS 5131-66-8), urinary metabolites such as the sulfate conjugate, propylene glycole and the parent compound were reported. More than 80% of the metaboltes of 1 -buthoxypropan-2 -ol are reported to be excreted within 48 hours.