Propyl 4-hydroxybenzoate

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Comparison of the metabolism of 10 chemicals in human and pig skin explants

Author:

C. Géniès, E. L. Jamin, L. Debrauwer, D. Zalko, E. N. Person, J. Eilstein,
S. Grégoire, A. Schepky, D. Lange, C. Ellison, A. Roe, S. Salhi, R. Cubberley, N. J. Hewitt, H. Rothe, M. Klaric, H. Duplan, C. Jacques‐Jamin

Year:

2018

Materials and methods

Test material

Specific details on test material used for the study:

propyl[14C] paraben (51 mCi/mmol, purity 99.3%)

Radiolabelling:

yes

Results and discussion

Any other information on results incl. tables

It has been reported that propyl paraben is converted to several metabolites. It can be directly conjugated to form propyl paraben‐sulfate and glucuronide; or conjugates can be formed after ester cleavage to 4‐hydroxybenzoic acid. In our studies,

this chemical passed through pig and human skin, such that ~50% Amount of propyl paraben and its metabolites in the medium after 24 h of the applied radioactivity was recovered into the culture medium after 24 hours. There was also extensive metabolism and nearly all propyl paraben applied to pig and human skin was subsequently present in the medium as metabolites.

Twelve metabolites were detected in the culture medium, of which the four major metabolites were identified by HRMS. The total percentage of metabolism was equivalent between pig and human skin (P > 0.05). The two major metabolites that were identified in pig skin were the glucuronide conjugate of 4‐hydroxybenzoic acid (12.8% of the applied dose) and the non‐

conjugated 4‐hydroxybenzoic acid, which represented 9.5% of the applied dose. The two other metabolites identified were 4‐ hydoxybenzoic acid glucuronide and propyl paraben sulfate, representing 5.0% and 2.7% of the applied dose, respectively.

There were metabolites that were not identified, representing between 1.68% and 34.8% of applied dose. All 12 metabolites that were produced in incubations with pig skin were also produced in human skin; however, the relative proportion of each differed. The same major metabolites were recovered in pig and human skin including 4‐hydroxybenzoic acid and the sulfate conjugate of the propyl paraben. The metabolites I‐IX were recovered in human skin in smaller

amounts than in pig skin and each represented less than 0.5% of the

applied dose.

.

	% Applied dose
	Pig	Human
Parent compound + metabolites	50.3 ± 1.1	56.0 ± 2.6
Propyl paraben (parent compound)	0.0	0.2 ± 0.2
Total metabolites	50.3 ± 1.1	55.8 ± 2.9
I (HBA‐glucuronides)	12.9 ± 0.3	0.02 ± 0.01*
II (maleic acid)	5.6 ± 0.3	0.5 ± 0.03*
III (not identified)	6.5 ± 0.4	0.3 ± 0.1*
IV (not identified)	3.6 ± 0.1	0.3 ± 0.06*
V (not identified)	1.3 ± 0.2	0.4 ± 0.04
VI (HBA‐glucuronides)	5.0 ± 0.05	0.15 ± 0.03*
VII (not identified)	0.4 ± 0.05	0.3 ± 0.2
VIII (not identified)	0.1 ± 0.01	0.4 ± 0.04*
IX (not identified)	0.5 ± 0.1	0.3 ± 0.1
X (4‐HBA)	9.5 ± 0.6	42.09 ± 2.8*
XI (not identified)	2.3 ± 0.7	5.31 ± 0.9*
XII (propyl paraben sulfate)	2.7 ± 1.4	5.67 ± 0.3*

HBA, hydroxybenzoic acid.

Amounts of metabolites in the medium expressed as a percentage of the

applied dose, mean ± SEM, four donors, n = 1 per donor.

*Statistical difference between pig and human skin (P < 0.05)

The human and pig skin explants incubated in short‐term culture

were shown able to metabolize chemicals via pathways known to

involve phase I and phase II XMEs. Phase I XME‐mediated pathways

included CYPs, evident as the metabolism of 7‐EC, and esterases,

demonstrated by the efficient biotransformation of propyl paraben.

A comparison of the metabolism of propyl paraben using pig and human skin showed that the extent of metabolism after 24 hours

was close and the same metabolites were produced by both species; however, the relative amounts of each metabolite differed considerably. These results are in accordance with the work of Jewell et al. (2007) showing that pig skin has a higher ability to metabolize parabens compared to human skin; however, they concluded that pig skin was still very close to human skin and can be used as an alternative to human skin for metabolism studies. As with propyl paraben, there were species differences observed in the metabolism of vanillin. This was with respect to the major metabolite, which indicated that Odemethylation is a predominant pathway in pig skin, whereas, aldehyde oxidase‐mediated metabolism is a major pathway in human skin.

Limitation of teh study: smal sample number

Applicant's summary and conclusion

Executive summary:

In summary this stidy showed that of the dose applied, 56% penetrated through human skin into receptor fluid. The majority of that (42%) was pHBA, indicating the action of carboxylesterases and 5.6% was sulphonated propyl paraben. However, there appears to be less of a capacity in human skin for p-HBA glucuronidation than in pig skin. pHBA is not regarded as toxic and would be rapidly cleared by other conjugation pathways in humans. Crucially, the vast majority of the applied dose in human skin that reached the receptor fluid was metabolised and only a very small amount, 0.2% of the dose reaching receptor fluid was free propyl parabens. All other metabolites are expected to be Phase 2 metabolites of either propyl paraben or pHBA that would be cleared very rapidly by the body via urine excretion. It is also possible that there is a very small amount of residual propyl paraben within the skin at the end of the experiment, and this represents a small uncertainty.