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EC number: - | CAS number: -
- 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
Dermal absorption
Administrative data
- Endpoint:
- dermal absorption in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 6th April 2017 - Experimental Termination 17th April 2017 Report Issued 5th June 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 428 (Skin Absorption: In Vitro Method)
- Deviations:
- no
- GLP compliance:
- no
- Remarks:
- This study was not conducted in compliance with Good Laboratory Practice but was performed according to the approved protocol and any amendments, and followed applicable internal Cyprotex SOPs.
Test material
- Test material form:
- liquid
- Remarks:
- Pale to yellow
- Details on test material:
- Chemical name: Reaction mass of N-[2-(2-hydroxyethoxy)ethyl]acetamide and Glycerol
Lot#: 1436088
Expiration Date: 10 August 2019
Molecular Weight: 147.17
Stability: 24 Months
Storage: RT in dark
- Specific details on test material used for the study:
- 12.4.1. N-[2-(2-hydroxyethoxy)ethyl]acetamide
• CAS#: 118974-46-2
• Molecular Weight: 147.17
• Log Pow: The average measured log Pow value for the test substance, as determined from the test, was <0. As an estimation, the log Pow value was calculated to be 2.7 by extrapolation.
• Stability: 24 Months
• Solubility: At least 369.5 mg/mL in water as per the Sponsor.
12.4.2. Formulation
• 3H-N-[2-(2-hydroxyethoxy)ethyl]acetamide 1 mCi/mL in ethanol (see Appendix E)
o Radiochemical Purity: >99% by HPLC
o Chemical Purity: Product identity confirmed by HPLC co-elution with Authentic Standard and Mass Spectroscopy
o Specific Activity: 9.6 Ci/mMole by Mass Spec.
o Lot#: 173-048-000
o Source: ViTrax Co. (Placentia, CA 92870)
o Cat#: VC 100
• Reaction mass of N-[2-(2-hydroxyethoxy)ethyl]acetamide and glycerol
o Lot#: 1436088
o Expiration Date: 10 August 2019
12.4.4. Preparation: The radiolabeled test material was produced by and purchased from ViTrax Co. (Placentia, CA 92870) as requested by the Sponsor. A 10 mL aliquot of radio inert ElfaMoist AC was placed into a 50 mL conical tube. Enough radiolabeled test material was spiked into the aliquot to produce a stock that delivered approximately 243,763DPM per 6.4 µL dose (an addition of approximately 10-3 of original amount of test material). The spiked aliquot was vortexed for approximately 2 minutes and then tested for homogeneity of radiolabel by measuring the radioactivity, in DPM, in 10 µL aliquots of the mixture obtained from 3 different places in the mixture. The samples collected from the preparation were within ±5% of the mean; therefore, the preparation was considered homogeneous. The results are presented in the table below.
12.4.5. Justification of Use: The formulation that was used is the marketed formulation. - Radiolabelling:
- yes
Administration / exposure
- Details on in vitro test system (if applicable):
- 12.5. Other Materials
12.5.1. Human Cadaver Thigh Skin: Dermatomed (approximately 0.75 mm thickness) human cadaver thigh tissue from a single donor were received flash frozen from SciKon Innovation, Inc. (Durham, NC 27709) and stored at -80⁰C, as directed, until use. The barrier quality of the skin sections were assessed with transepithelial water loss (TEWL) measurements using a Vapometer SWL5 (Delfin Technologies) after placement onto the Franz Cells. All skin sections had an acceptable barrier function as indicated by TEWL readings of ≤ 11 g/m2/hour with values that ranged from 6.9 to 10.9 g/m2/hour.
• Skin Lot 151004: Scikon Innovation, Inc. Causcasian Female Aged 64, Exp: 09Mar2018
12.5.2. Miscellaneous Reagents:
• Phosphate Buffered Saline: Gibco, Cat # 10010-023, Lot# 1754017, Exp: October 2017; and Mattek, Cat # Dulbecco’s Phosphate Buffer, Lot# 041916PLA, Exp: 19April2017
• Sodium Azide: Sigma, Cat #S2002, Lot# MKBR3666V, Exp: Feb 2019
• Brij 98®: ACROS, Cat # 347181000, Lot # A0373841, Exp: Jun 2021
• Scintillation Fluid: Perkin-Elmer, Cat #: 6013329, Lot# 77-16191, Exp: 01Dec2017
• Ethanol: Spectrum, Cat #: E1424, Lot# 1FF0319, Exp: 22 Jan 2019
• Acetone: Sigma-Aldrich, Cat# 270725, Lot# SHBB8538V, Exp: July 2017
• Soluene-350: Perkin-Elmer, Cat#: 6003038, Lot#: 24-16131, Exp: 01Oct2017
12.6. Receiver Fluid
12.6.1. Test Material Receiver Fluid: PBS pH 7.4 with 0.1% Brij 98® and 1mM NaN3
12.6.2. Reference Control Receiver Fluid: PBS pH 7.4 with 0.1% Brij 98® and 1mM NaN3
Results and discussion
Percutaneous absorptionopen allclose all
- Time point:
- 12 h
- Dose:
- Absorbed dose
- Parameter:
- percentage
- Absorption:
- 0.057
- Key result
- Time point:
- 24 h
- Dose:
- Absorbed dose
- Parameter:
- percentage
- Absorption:
- 0.382
- Key result
- Time point:
- 24 h
- Dose:
- Absorbable dose
- Parameter:
- percentage
- Absorption:
- 0.562
Any other information on results incl. tables
Mass Balance (%recovery)
For each Franz Cell, amounts of each test material(DPM)in the following compartments: initial donor (MDonor(0)), tissue washes (MWashes), tape strip extracts (MTape strips), skin extracts (Mskin), receiver fluid (MReceiver) and Franz Cell rinse and Donor Swab (MRinse) at the end of the experimental period were measured for all test material and control chemicals. Test material mass balances in the system were calculated with Equation 1.
Mass Balance = (MReceiver) + (MWashes) +(MTape strips) + (Mskin) + (MRinse) X 100 _______________________________________________
(MDonor(0))
For each Franz Cell testing reference controls, amounts (DPM) of each reference control in the following compartments were measured: initial donor (MDonor(0)), final dose (MDonor(F)), tissue washes (MWashes), skin extracts (Mskin), and receiver fluid (MReceiver) at the end of the experimental period. Reference control mass balances in the system were calculated with Equation 2.
Mass Balance = (MReceivers) +(MWashes) +(MFinal Dose) +(Mskin) X 100
_____________________________________
(MDonor(0))
Table 1a and Appendices B and C present the mean and individual mass balance (percent recovery) values for the reference controls. Table 1b and Appendix D present the mean and individual mass balance values for N-[2-(2-hydroxyethoxy)ethyl]acetamide when formulated as ElfaMoist AC.
Table 1a. Mass Balance (% Recovery) for14C-Benzoic Acid and14C-Mannitol Treated-Franz Cells |
|||||
Reference Controls Mass Balance (% Recovery) per Franz Cell |
|
||||
Reference |
Replicate 2 |
Replicate 2 |
Replicate 3 |
Replicate 4 | Mean (Std) |
Benzoic acid |
101.8% |
101.9% |
102.5% |
99.7% | 101.5% (1.2%) |
Mannitol |
98.0% |
99.2% |
98.1% |
98.2% | 98.4% (0.6%) |
§Arithmetic Mean, N=4 |
All four replicates treated with each of14C-Benzoic Acid or14C-Mannitol showed acceptable mass balance values of 100% ± 10%. When the mass balance falls into the acceptable range, the permeability data generated is regarded as being representative of the test material’s actual behavior in the test system.
Table 1b. Mass Balance (% Recovery) for Franz Cells Treated with 3H-N-[2-(2-hydroxyethoxy)ethyl]acetamide Formulated as ElfaMoist AC |
||||
Mass Balance (% Recovery) per Franz Cell |
Mean§(Std) |
|||
Replicate 1 |
Replicate 2 |
Replicate 3 |
Replicate 4 |
|
99.7% |
103.5% |
85.6% |
97.6% |
96.6% (7.8%) |
§Arithmetic Mean, N=4 |
Three of four Franz Cells treated with ElfaMoist AC had acceptable mass balances of 100% ± 10% for materials that were radiolabeled. The low mass balance for Replicate 3 was most likely due to variability in the dose volume applied since the greatest difference in material distribution between the Franz Cells was in the sum of the washes; replicate 3’s washes produced 81.9% of the initial dose while the other 3 replicates’ totals were all above 93%.
Table 1c. Mean§ Percent Initial Dose of All Franz Cell Compartments and Total Mass Balance* of All Franz Cells Treated with 3H-N-[2-(2-hydroxyethoxy)ethyl]acetamide Formulated as ElfaMoist AC |
|||||
Mean % Initial Dose per Franz Cell Compartment |
Total Mass Balance | ||||
Reciever | Washes | Tape Strips | Skin | Franz Cell Rinses | |
0.382% | 92.853% | 3.276% | 0.094% | 0.0040% | |
§Arithmetic Mean, N=4 *The sum of all mean percent intitial dose values of each Franz Cell compartment |
Cumulative Transfer into the Receiver and Material Distribution
Table 2 presents the mean and individual mass of test material transferred into the receiver at each specified time point as a percent of initial dose. Table 3 presents the mean and individual test material distribution in each of the tape-strip groups and sum of all tape-strips as a percent of initial dose. Table 4 presents the mean and individual distribution in the skin extracts, the total absorbable dose (total test material present on or in the skin following washings), and total absorbed dose(amount of test material reaching the receiver buffer)as a percent of initial dose.
Table 2. Mean§and Individual Cumulative Percent of Initial Dose of
|
|||||||
Replicate |
Cumulative % of Initial Dose in the Receiver Chamber at Each Time Point |
||||||
1 Hr |
2 Hr |
4 Hr |
6 Hr |
12 Hr |
24 Hr |
||
Replicate 1 |
0% |
0% |
0% |
0% |
0.051% |
0.392% |
|
Replicate 2 |
0% |
0% |
0% |
0% |
0.103% |
0.384% |
|
Replicate 3 |
0% |
0% |
0% |
0% |
0.000% |
0.267% |
|
Replicate 4 |
0% |
0% |
0.041% |
0.002% |
0.073% |
0.487% |
|
Mean§ |
0% |
0% |
0.010% |
0% |
0.057% |
0.382% |
|
St Dev |
0% |
0% |
0.021% |
0.001% |
0.043% |
0.090% |
|
§: Arithmetic Mean, N=4
Grayed replicate had a mass balance of 100% ± 10% |
Table 3. Mean§and Individual Mass as a Percent of Initial Dose of |
|||||
Replicate |
Tape-Strip Group 1 |
Tape-Strip Group 2 |
Tape-Strip Group 3 |
Tape-Strip Group 4 |
Sum of All Tape Strips |
Replicate 1 |
1.401% |
1.639% |
0.030% |
NS |
3.069% |
Replicate 2 |
1.344% |
1.905% |
0.042% |
0.000% |
3.291% |
Replicate 3 |
2.668% |
0.733% |
0% |
NS |
3.402% |
Replicate 4 |
2.560% |
0.780% |
0% |
NS |
3.340% |
Mean§ |
1.993% |
1.265% |
0.018% |
0% |
3.276% |
St Dev |
0.719% |
0.596% |
0.021% |
0% |
0.145% |
§: Arithmetic Mean, N=4 Grayed replicate had a mass balance of 100% ± 10% NS: No Sample |
Table 4. Mean§and Individual Mass as a Percent of Initial Dose |
||||
Replicate |
Skin |
AbsorbableǂDose |
Absorbed* Dose |
|
Replicate 1 |
0.086% |
3.156% |
0.392% |
|
Replicate 2 |
0.763% |
3.367% |
0.384% |
|
Replicate 3 |
0.047% |
3.448% |
0.267% |
|
Replicate 4 |
0.165% |
3.505% |
0.487% |
|
Mean§ |
0.094% |
3.369% |
0.382% |
|
St Dev |
0.050% |
0.153% |
0.090% |
|
§: Arithmetic Mean, N=4 |
||||
Grayed replicate had a mass balance of 100% ± 10% |
||||
ǂAbsorbable Dose: Total test material present on or in the skin following washings *Absorbed Dose: Amount of test material reaching the receiver buffer at 24-hours |
1.1.Permeability Coefficient (Papp, cm/h, reference controls only)
For each Franz Cell treated with reference controls, initial donor mass (MDonor(0)) and final donor mass, cumulative mass in the receiver compartment (MReceiver) over the 24-hour incubation period were determined.
Permeability coefficients (P, cm/hr) for the reference controls are presented in Table 5 and Appendices B and C and were calculated with Equation 3.
Equation 3:
P= MR [VD]
__ ___
MD(0) [A.Δt]
where VDis the volume of the donor compartment and A is the area of exposed tissue. To calculate the Papp values, the cumulative transfer of the test material and each reference control into the receiver (MReceiver/MDonor(0)) over time (Δt) was graphed and the slopes of the linear portions of the graphs (R2≥ 0.99) were multiplied by VDand divided by the area of exposed tissue.
Table 5. Permeability Coefficient (Papp, cm/h) for14C-Benzoic Acid and14C-Mannitol |
|||||
Reference |
Replicate 1 |
Replicate 2 |
Replicate 3 |
Replicate 4 |
Mean§ (± Std) |
Benzoic Acid |
2.34x10-4 |
5.47x10-4 |
1.80x10-3 |
4.69x10-4 |
7.62x10-4 (7.03x10-4) |
Mannitol |
3.13x10-5 |
3.91x10-5 |
4.69x10-5 |
2.34x10-5 |
3.52x10-5 (1.01x10-5) |
§Arithmetic Mean, N=4 |
The skin sections acted as expected with respect to the permeability characteristics of the reference controls. As expected,14C-Benzoic Acid, the high permeability reference, penetrated the tissue cultures at a faster rate than14C-Mannitol, the low permeability reference.
1.1.Flux Values (µg transferred/cm2of skin/hour)
The flux (µg transferred/cm2/h) for3H-N-[2-(2-hydroxyethoxy)ethyl]acetamide through the skin was calculated. To derive these values, the total amount of test material in the receiver based on percent of initial dose divided by the area of exposed skin over time was graphed. The flux values are the resulting slopes from the linear portions of these graphs (R2 ≥ 0.99) and were calculated from data at time points starting at 6 hours. The flux values for the test material are presented in Table 6.
Table 6. Flux (µg transferred/cm2/h) for Treated-Franz Cells over the 24-Hour Exposure Period |
||||
Replicate 1 |
Replicate 2 |
Replicate 3 |
Replicate 4 |
Mean§(Std) |
327.64 |
249.53 |
256.58 |
397.51 |
307.82 (69.43) |
§Arithmetic Mean Grayed replicate had a mass balance of 100% ± 10% |
Applicant's summary and conclusion
- Conclusions:
- In general, less than 0.5% of the initial dose was absorbed (mass of test substance reaching the receiver fluid) over the 24-hour exposure. There was at least a 4-hour lag phase where no material was found in the receiver chamber after which only small amounts of test material appeared. The overall mean flux rate, calculated from values after 6 hours of exposure, was 307.82 ± 69.43 µg transferred/cm2 skin/hour.
- Executive summary:
The test substance “Reaction mass of N-(2-hydroxyethyl)alkyl] alkylamide and glycerol” has been tested for skin absorption potential in an in vitro test performed according to OECD428, and using radiolabelled material.
The mass balance values for 8 of 8 Franz Cells treated with the two reference control materials were considered acceptable since they were within the OECD acceptable range for radiolabelled materials (100 ± 10%; OECD 2004). Individual recoveries (Table 1a and Appendices B and C) for Franz Cells with acceptable mass balances ranged from 99.7% to 102.5% for 14C-Benzoic Acid and 98.0% to 99.2% for 14C-Mannitol. Permeability coefficients generated by the high permeability reference control, 14C-Benzoic Acid (mean of 7.62x10-4 ± 7.03x10-4 cm/hour), and the low permeability reference control, 14C-Mannitol references (mean of 3.52x10-5 ± 1.01x10-5 cm/hour) indicated the skin samples behaved as expected when exposed to the reference controls (Table 5 and Appendices B and C). These Permeability Coefficient (Papp) values also fell within the historical range of Papp for this assay for Benzoic Acid (range of 1.56x10-5 to 1.75x10-2 cm/h, mean and standard deviation of 5.42x10-3 ± 3.99x10-3 cm/h; N=45) and Mannitol (range of 0.0 to 1.95x10-3 cm/h, mean and standard deviation of 2.73x10-4 ± 4.88x10-4 cm/h; N=40) Mass balance values that were within the OECD acceptable range indicated that the distribution of the test material in these Franz Cells are representative of the actual permeability behaviour of the material. Data should be interpreted with this in mind.
The mean mass balance for all Franz Cells was 96.6% (Table 1b); this was also the total mass balance value when the mean percents of initial dose of each of the Franz Cell compartments were added together (Table 1c). Three of four Franz Cells treated with test substance had acceptable mass balances of 100% ± 10% for materials that were radiolabelled. The low mass balance for one replicate (replicate 3; 85.6%) was most likely due to variability in the dose volume applied since the greatest difference in material distribution between the Franz Cells was in the sum of the washes; replicate 3’s washes produced 81.9% of the initial dose while the other 3 replicates’ totals were all above 93%. Since the material distribution of all the Franz Cells treated with test material was very similar except for the washes, the permeability behaviour of the test material in all four Franz Cells can be considered as the same.
The majority of the 3H N-[2-(2-hydroxyethoxy)ethyl]acetamide in the substance applied dose remained on the surface of the skin mounted on all four Franz Cells and was removed by the three washes at the end of the 24-hour exposure (Appendix D). Little to no test material penetrated into the receiver chamber. For three of four Franz Cells, the test material was below detectable limits for the first 6 hours of the exposure; the remaining Franz Cell showed only 0.041% of the initial dose was absorbed into the receiver by 4 hours into the exposure. At 12 hours, 3 of 4 Franz Cells showed 0.103% or less of the initial dose was absorbed into the receiver. After 24-hours, the mean cumulative amount present in the receiver, also considered the absorbed dose, had increased to 0.382%±0.090% for all four Franz Cells.The flux was calculated from the amounts of test material appearing from 6 to 12 hours into the exposure and were similar for all Franz Cells ranging from 249.53 to 397.51 µg transferred/cm2/hour with a mean of 307.82±63.43 µg transferred/cm2/hour (Tables 2 and 6, Appendix D).The total amounts of the test material extracted from the tape strips as a percent of initial dose from each Franz Cell ranged from 3.069% to 3.402% (mean of 3.276%±0.145%) indicating little test material was available in the stratum corneum/epidermis for possible further absorption.
The amounts of test material in the tape-stripped skin was also small with individual values that ranged from 0.047% to 0.165% of initial dose (mean of 0.094%±0.050%, Table 4 and Appendix D). The total amounts present in the skin washes (Appendix D) also reflected these data in that washes from skin contained the majority of the dose with percents of initial dose ranging from 81.9% to 99.8%.
Conclusions:
Three of four Franz Cells treated with 3H-N-[2-(2-hydroxyethoxy)ethyl]acetamide when formulated as the product ‘Reaction mass of N-(2-hydroxyethyl)alkyl] alkylamide and glycerol’ had acceptable mass balances of 100% ± 10% for test materials that were radiolabelled. The low mass balance for one replicate (replicate 3; 85.6%) was most likely due to variability in the dose volume applied since the greatest difference in material distribution between the Franz Cells was in the sum of the washes. Since the material distribution of all the Franz Cells treated with the test substance was very similar except for the washes, the permeability behaviour of the test material in all four Franz Cells can be considered as the same.
In general, less than 0.5% of the initial dose was absorbed (mass of test substance reaching the receiver fluid) over the 24-hour exposure. There was at least a 4-hour lag phase where no material was found in the receiver chamber after which only small amounts of test material appeared. The overall mean flux rate, calculated from values after 6 hours of exposure, was 307.82 ± 69.43 µg transferred/cm2 skin/hour. The amount of test material extracted from the tape strips representing material in the stratum corneum/epidermis ranged from 3.069% to 3.402% of the initial dose. The mass of test material found in the tape-stripped skin ranged from 0.094%±0.050% of initial dose. Overall, these data indicated little test material was absorbed into the receiver over the 24-hour exposure period and little test material was considered as absorbable (mass of material present in or on the washed skin); therefore, the majority of the test material in the initial dose remains on the surface of the skin over the 24-hour exposure period.
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