4-hydroxybenzoic acid

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

After oral administration of 5 g 4 -HBA every 6 hours up to a total dosage of 20 g to a human/humans. 70% were excreted unchanged with the urine. According to the authors this dosage is the maximum dosage that the human body is able to dispose of in the course of 24 hours (Power and Sherwin, 1927).

Oral dosages of 1.0 g/kg bodyweight were given to groups of 3 dogs. After administration of 4-HBA and Methylparaben (the methyl ester of 4 -HBA) the same concentrations of free 4 -HBA and the same kinetics for the elimination of 4 -HBA were found in the plasma (Jones et al., 1956).

Methyl and Ethyl paraben represent the alkyl esters of 4-HBA with methanol and ethanol, respectively. Both substances have been shown experimentally to undergo metabolism to 4-HBA (Jones et al., 1956; Aubert, 2009 cited in SCCS/1348/10 and SCCS/1446/11; Kiwada et al., 1980; Jewell et al., 2007; Derache and Gourdon, 1963; Phillips et al., 1978).

Available studies reveal that after oral administration of Methylparaben only traces of the unchanged compound were found in the plasma.

After the oral administration of 4-HBA to dogs 94% of the dosage were recovered in the urine, 40.1% as free 4-HBA, 30.0% as glucuronic acid conjugate (Jones et al., 1956).

After the oral administration of Methylparaben to dogs 89% of the dosage were recovered in the urine, 21.3% as free 4-HBA, 35.1% as glucoronide acid conjugate (Jones et al., 1956).

After the oral administration of Ethylparaben to dogs 66% of the dosage were recovered in the urine. The major part of the recovered test substance was found as free p-hydroxybenzoic acid (12.3%) and as conjugate with glucuronic acid (32.5%) (Jones et al., 1956).

Obviously methylparaben is degraded to 4-HBA in the stomach.

After intravenous administration of¹⁴C-Ethylparaben to rats (2 mg/kg bw) the total radioactivity in the blood of ethylparaben decreased rapidly (Kiwada et al., 1980). The activity detected at 3 min was as low as 5 % of the total activity and was below the detectable limit (5 ng/mL blood) at 45 min after administration. The course of ethylparaben, p-hydroxybenzoic acid as well as the course of corresponding conjugates (p-hydroxyhippuric acid, p-hydroxybenzoil glucuronid, p-carboxyphenyl sulfate) showed blood concentrations per dose below the detection limit at 1.5 hours after administration of ethylparaben. Metabolism (including hydrolysis and conjugation) is excellent/efficient in ethylparaben administration. Nearly similar results were observed after intraduodenal administration of¹⁴C-Ethylparaben in the same dose level to rats. The ester form was less detected after intraduodenal than intravenous administration. The authors have reported rapid hydrolysis not only in blood but also in the liver and other tissues and the intestine after intraduodenal administration. Further,¹⁴C labelled 4-HBA was administered (to rats at 2 mg/kg bw) intravenous and intraduodenal by Kiwada et al. (1980). Blood levels of 4-HBA and the above stated conjugates were similar over time when comparing administrations of 4-HBA and ethylparaben, with the exception that the initial 4-HBA blood concentrations where higher with 4-HBA administration than with ethylparaben. For all sets of experiments 4-HBA and the conjugates were rapidly eliminated from the blood. These findings support theread-across rationale (Appendix to the CSR and attached in section 13 of the IUCLID-Dossier).

Short-, mid- and long-chain parabens in rats are almost exclusively hydrolysed to 4-HBA in the skin after topical application and in the systemic circulation after oral or subcutaneous administration as well. After dermal administration, they are partly (15 to 27%) absorbed and rapidly eliminated. Blood analysis only showed the presence of 4-HBA (Aubert 2009, cited in and reviewed by the Scientific Committee on Consumer Safety in SCCS/1348/10 and confirmed in SCCS/1446/11 and by the Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung (BfR)) (BFR, 2011). Metabolism in the skin and in the body leads to hydrolysis of esters of 4-HBA. Therefore, 4-HBA as hydrolysis product is observed predominantly, particularly when using esters of short-chain alcohols like methanol or ethanol (Ye et al., 2006). EFSA (2012) concludes that methylparaben and ethylparaben is hydrolysed in vivo based on publications such as Heim et al. (1957) and Jones et al. (1956).

The dermal absorption of radiolabelled 4 -HBA through the skin of 29-day-old female rats was examined over a 120 hour period (Hughes and Hall, 1997).

The dermal absorption was minimal, 4% of the dosage. The recovery of the total radiolabelled dosage was 99.92%. 95.9% remained at the treated skin site.

Obviously 4-HBA is not resorbed through the intact skin in relevant amounts.

Details on toxicokinetics are also summarised in the read-across rationale (Appendix to the CSR (attached in section 13 of the IUCLID-Dossier)).