Phosphonic acid, mixed C12-20-alkyl and C14-18-unsatd. alkyl derivs.

Dermal absorption

Administrative data

Endpoint:

dermal absorption

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

January 2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Generally accepted equations for the approximation of determinants of dermatological and systemic penetration after topical application (Kp and Jmax) were used.

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

A new method for estimating dermal absorption from chemical exposure. 1. General approach

Author:

Cleek RL, Bunge AL

Year:

1993

Bibliographic source:

PMID 8483831 Pharmaceutical Research ISSN 0724-8741 10(4):497–506

Reference 2

Reference Type:

other: Software

Title:

Estimation Programs Interface for Microsoft Windows, EPI Suite version 4.1

Author:

EPA DERMWIN v2.01

Year:

2010

Bibliographic source:

U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington DC, U.S.A. & Syracuse Research Corporation (SRC)

Reference 3

Reference Type:

publication

Title:

Molecular Size as the Main Determinant of Solute Maximum Flux Across the Skin

Author:

Magnusson BM, Anissimov YG, Cross SE, Roberts MS

Year:

2004

Bibliographic source:

PMID 15102090 DOI 10.1111/j.0022-202X.2004.22413.x Journal of Investigative Dermatology 122(4):993-9

Reference 4

Reference Type:

publication

Title:

Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients

Author:

Kroes R, Renwick AG, Feron V, Galli CL, Gibney M, Greim H, Guy RH, Lhuguenot JC, van de Sandt JJ

Year:

2007

Bibliographic source:

PMID 17664037 DOI 10.1016/j.fct.2007.06.021 Food Chem Toxicol 45(12):2533-62

Reference 5

Reference Type:

publication

Title:

Predicting Skin Permeability

Author:

Potts RO, Guy RH

Year:

1992

Bibliographic source:

PMID 1608900, DOI 10.1023/A:1015810312465, Pharmaceutical Research (ISSN 0724-8741) 9(5):663-9.

Reference 6

Reference Type:

publication

Title:

Drug structure–transport relationships

Author:

Roberts MS

Year:

2010

Bibliographic source:

PMID 21107662 DOI 10.1007/s10928-010-9174-0 J Pharmacokinet Pharmacodyn 37(6):541–573

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: EPA U.S. (2004). Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment). Document References EPA/540/R/99/005, OSWER 9285.7-02EP and PB99-963312.

Deviations:

yes

Remarks:

In addition to the guideline generally accepted Jmax estimation and evaluation schemes were used

Principles of method if other than guideline:

The DERMWIN v2.01 software estimates the dermal permeability coefficient (Kp) or skin permeability coefficient, which is a flux value normalized for concentration [cm/h]. It represents the rate at which a chemical penetrates the skin. A general equation for approximation of the value, used in as well in DEREK (rulebase software, Lhasa Ltd) has been published by Potts & Guy (1992). The Kp estimation methodology used in DERMWIN is taken directly from the EPA (2004) document (and supplemental Excel spreadsheet) and represents a minor refinement of the general equation. The estimation methodology in DERMWIN v2.01 is an update of the method and equations used in previous versions of DERMWIN that were based on the EPA (1992) document. A correction of the Kp calculation taking into account the contribution of living skin layers (viable epidermis and dermis) according to Cleek & Bunge (1993) has been proposed for very lipophilic chemicals.
Another determinant of dermatological and systemic penetration after topical application is the dermal delivery or flux of solutes into or through the skin. The maximum dose of a solute able to be delivered over a given period of time and area of application is defined by its dermal maximum flux, Jmax. Kroes et al (2007) demonstrate that Jmax can be derived from the Kp and the water solubility. Magnusson et al (2004) found the molecular weight to be the dominant determinant of Jmax and proposes another estimation method. Jmax should be a constant as long as the chemical is at its maximum thermodynamic activity in the vehicle, i.e. that it is a saturated solution or the pure compound (Kroes et al 2007). Kp and Jmax are derived by these methods and evaluated by the scheme proposed by Kroes et al (2007).
- EPA U.S. Environmental Protection Agency (1992). Dermal Exposure Assessment: Principles and Applications. U.S. EPA Exposure Assessment Group, Office of Health and Environmental Assessment, Washington, DC, U.S.A., Interim Report Self-published January 1992, Document Reference EPA/600/8-91/011B. 389 p.
- EPA U.S. Environmental Protection Agency (2004). Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment). U.S. EPA, Office of Superfund Remediation and Technology Innovation, Washington, DC, U.S.A., Self-published July 1994, Document References EPA/540/R/99/005, OSWER 9285.7-02EP and PB99-963312. 156 p. (Available online at: http://www.epa.gov/oswer/riskassessment/ragse/index.htm)

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phosphonic acid, mixed C12-20-alkyl and C14-18-unsatd. alkyl derivs.

EC Number:

300-326-6

EC Name:

Phosphonic acid, mixed C12-20-alkyl and C14-18-unsatd. alkyl derivs.

Cas Number:

93925-25-8

Molecular formula:

Complex

IUPAC Name:

Phosphonic acid, mixed C12-20-alkyl and C14-18-unsatd. alkyl derivs.

Test material form:

liquid: viscous

Results and discussion

Absorption in different matrices:

QSPR calculation
Dermal permeability coefficient (Kp):
Equation 1, DERMWIN v2.1: 1.48 to 31.45 cm/h for high and low molecular weight representative structures, respectively
Equation 2, Potts & Guy (1992): 2.62 to 72.51 cm/h for high and low molecular weight representative structures, respectively
Equation 3, Cleek & Bunge (1993): 0.10 to 0.14 cm/h for high and low molecular weight representative structures, respectively - used for Jmax calculation according to Kroes et al (2007).

Dermal maximum flux (Jmax):
Equation 4, Kroes et al (2007): 1.0 to 1.4 pg/(cm²∙h) for high and low molecular weight representative structures, respectively (based on corrected Kp, Cleek & Bunge 1993)
Equation 5, Magnusson et al (2004): 0.62 pg/(cm²∙h) to 11,386 pg/(cm²∙h) for high and low molecular weight representative structures, respectively

Dermal absorption category:
The UVCB clearly falls into the “low” skin absorption category and the worst case default absorbed dose per 24 h can be expected not to exceed 10 % of the neat UVCB.

Resulting dose:
For a standard person (1.75 m body height, 75 kg body weight, 1.84 m² body surface) for 24 h in contact with the pure UVCB on 10 % of his body surface, the absorbed dose would be as low as 0.6 μg/kg bw according to Equation 5 (Kroes et al 2007).

Applicant's summary and conclusion

Conclusions:

Estimated dermal permeability coefficient, Kp ca. 0.10 to 0.14 cm/h and dermal maximum flux, Jmax ca. 1.0 to 1.4 pg/(cm²∙h); “low” skin absorption category and worst case absorption rate not exceeding 10 % per 24 h

Executive summary:

To assess on the dermal absorption of the test item generally accepted equations for the approximation of determinants of dermatological and systemic penetration after topical application (Kp and Jmax) were used. The calculations were made with the extrema of the molecular weights (MW) contained.

Three methods were used for the computation of the dermal permeability coefficient (Kp). The dermal maximum flux (Jmax) was estimated on the basis two independent approaches, one starting from the most reliable Kp values and considering water solubility while the second one uses MW as sole determinant.

The calculations suggest that high lipophilicity correction is relevant for the UVCB, which is supported by applicability domain considerations. The accordingly estimated Kp (calculated using Kow and MW) ranges from 0.10 to 0.14 cm/h and the Jmax from 1.0 to 1.4 pg/(cm²∙h) for high and low molecular weight representative structures, respectively. The model using only MW predicts a larger range, whereof the upper extreme value keeps however clearly below 0.1 μg/(cm²∙h), which represents the reference value for categorization.

Considering the Log Kow and MW above 5 and 300 g/mol, respectively, the results clearly place the UVCB in the “low” skin absorption category and the worst case default absorbed dose per 24 h can be expected not to exceed 10 % of the neat UVCB.