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EC number: 260-252-4 | CAS number: 56539-66-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- 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.
- 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
- Guideline:
- OECD Guideline 428 (Skin Absorption: In Vitro Method)
- Qualifier:
- according to guideline
- 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
- Guideline:
- other: - OECD Guidance Notes on Dermal absorption, Draft 22 October 2010
- Qualifier:
- according to guideline
- Guideline:
- other: - European Commission Guidance Document on Dermal Absorption – Sanco/222/2000/Rev. 7 (19 March 2004)
- GLP compliance:
- yes (incl. QA statement)
- 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
- 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.
Referenceopen allclose all
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.
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
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.
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