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Administrative data

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: GLP Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Principles of method if other than guideline:
The aim of this study was to determine the absorption rate of the test substance through the skin after a single topical application. The study was performed in vitro using dermatomed membranes of the flank of pigs.
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
N-(n-octyl)-2-pyrrolidinone
EC Number:
403-700-8
EC Name:
N-(n-octyl)-2-pyrrolidinone
Cas Number:
2687-94-7
Molecular formula:
C12 H23 N O
IUPAC Name:
1-octylpyrrolidin-2-one
Details on test material:
- Name of test material (as cited in study report): N-Octylpyrrolidon; Test substance No.: 01/0525-2
- Analytical purity: 99.4 corrected area-%
- Lot/batch No.: B408 v. 11.04.03
- Stability: The sponsor guaranteed the storage stability of the test substance up to April 2005 (see analytical reports concerning a comparable batch, Nos.: 0/91/48723 and 0/92/48677).
- Storage condition of test material: Room temperature
- Homogeneity: The homogeneity is guaranteed due to the high purity; additionally the homogeneity is provided by shaking the test substance container.

Test animals

Species:
guinea pig

Administration / exposure

Type of coverage:
other: not applicable
Vehicle:
water
Duration of exposure:
24 hours
Doses:
0.015 and 10 mg/cm²
Details on study design:
see below: Any other information on materials and methods
Details on in vitro test system (if applicable):
see below: Any other information on materials and methods

Results and discussion

Total recovery:
- Total recovery: mean total recovery was 96.1 % (high dose) and 98.1 % (low dose)
- Recovery of applied dose acceptable: yes

Any other information on results incl. tables

RESULTS

 

RECOVERY

The mean total recovery measured in diffusion cells equipped with pig skin fulfilled the OECD quality criteria. The individual values ranged from 93.5 to 97.6 % for the high dose and from 90.7 to 107.9 % for the low dose. Regarding the non-absorbed dose, about 3.3 % of the high dose of the test substance was found in the donor compartment, while 29.0 % and 5.2 % of dose were found in the washings and tape stripping of the skin membranes, respectively. In contrast, no test substance of the 10w dose was found neither in the donor compartment nor in the skin membrane washings or tape stripping. About 26.9 % of dose (high dose) and 4.7 % of dose (low dose) were associated with the skin membrane. About 31.7 % of dose (high dose) was recovered from the receptor fluid and receptor compartment, which is considered to represent the absorbed dose, while the major amount of test substance (93.5 % of dose) of the low dose was found in the receptor fluid or receptor compartment.

 

ABSORPTION KINETICS

The mean absorption rate for N-Octylpyrrolidon corresponding to the slope of the cumulative absorbed dose curve over time was about 115.6 pg/(cm² * h) for the high dose and 7.2 pg/(cm² * h) for the low dose, using linear regression analysis for the penetration within 4 to 24 hours (high dose) or within the first hour (low dose). This is equivalent to a permeability coefficient (Kp) of about 1.2 * 10-4(high dose) or 4.9 * 10-3(low dose) taking into account the applied concentration. According to the categorization schemes suggested by Marzulli et al. 1969 and Barber et al. 1995 these penetration rates are considered to indicate moderate diffusion rate for the high dose and fast diffusion rate for the low dose. Furthermore the evaluation of the absorption kinetic indicated a mean lag time of about 1.7 and 0 hours for the high and low dose, respectively. The cumulative absorbed dose found in the receptor fluid after the 24-hour exposure period was about 24.4 % (high dose) and 95.1 % (low dose) of the applied dose.

 

Synopsis

The figure presenting the mean cumulative absorbed dose over time in diffusion cells equipped with dermatomed membranes from pig skin is shown in the study report. The absorption vs. time plot of the high dose showed an almost linear behaviour of the absorption curve for dermatomed pig membranes during the whole study period. The virtually individual absorption kinetics for the perspective diffusion cells indicated a linear correlation of the mean cumulative absorbed dose time from 4-24 hours. The absorption vs. time plot of the low dose indicated an almost linear behaviour of the absorption curve for the first hour after application. A slight decrease in absorption rate was observed 2-4 hours after application, which was more pronounced towards the end of the exposure time.

 

DISCUSSION

The dermal penetration of N-Octylpyrrolidon through dermatomed pig membranes in vitro was examined after application of the undiluted test substance (high dose) and a 0.15 % test substance preparation in doubly distilled water (low dose). The target dose of about 10 mg or pL/cm² was achieved well. The mean total recovery was 96.1 % (high dose) and 98.1 % (low dose) of the applied dose and therefore fulfilled the OECD quality criteria (100 ± 10 %). Regarding the non-absorbed dose, about 3.3 % of the high dose were found in the donor compartment, while 29.0 % and 5.2 % of dose were found in the washings and tape stripping of the skin membranes, respectively. In contrast, no test substance of the low dose was found, neither in the donor compartment nor in the skin membrane washings or tape stripping indicating virtually complete absorption. About 26.9 % of dose (high dose) and 4.7 % of dose (low dose) were associated with the skin membrane. About 31.7 % of dose (high dose) was recovered from the receptor fluid and receptor compartment, which is considered to represent the absorbed dose, while almost all of test the test substance (93.5 % of dose) of the low dose was found in the receptor fluid or receptor compartment. Furthermore the evaluation of the absorption kinetic indicated a mean lag time of about 1.7 and 0 hours for the high and low dose, respectively. The absorption vs. time plot for the high dose showed an almost linear behavior of the absorption curve for dermatomed pig membranes during the whole study period. The absorption vs. time plot for the low dose indicated a linear behavior of the absorption curve for the first hour after application. A slight decrease in absorption rate was observed 2 - 4 hours after application, which was more pronounced towards the end of the exposure time. The mean absorption rate for N-Octylpyrrolidon corresponding to the slope of the cumulative absorbed dose curve over time was about 115.6 pg/(cm2* h) for the high dose and 7.2 pg/(cm2* h) for the low dose. This is equivalent to a permeability coefficient (Kp) of about 1.2 * 10-4 (high dose) or 4.9 * 10-3 (low dose) taking into account the applied concentration. According to the categorization schemes suggested by Marzulli et al. (1969) and Barber et al. (1995), the penetration rates found in this study indicated moderate diffusion for the high dose and fast diffusion for the low dose. The findings reported, indicate a faster penetration of N-Octylpyrrolidon through dermatomed pig skin, when applied as an aqueous solution. This is in accordance with literature data. Using human full thickness skin, Venier et al. showed higher Kp values for different glycol ethers, when applied as a 50 % aqueous solution compared to the application of the undiluted solvents (Venier et al. 2004). In addition, for some pesticides a higher partition into pig stratum corneum is reported, when applied as solutions in water, compared to solutions in ethanol (van der Merwe et al. 2005).

Applicant's summary and conclusion

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