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Toxicokinetic data on methylparaben and its sodium salt have shown that it is completely absorbed after oral ingestion, hydrolysed to p-Hydroxybenzoic acid, conjugated and excreted in urine. There is no evidence of accumulation. Dermal absorption data show, that Methylparaben penetrates human skin as well as rat and minipig skin. Within 24 h, a dermal absorption of 67.6% was observed in rat skin and 84.7% in human skin.

Key value for chemical safety assessment

Additional information

There is only one study available on toxicokinetics for sodium methylparaben (Tsukamoto, 1960). However, there are reliable data on methylparaben which is considered suitable for read-across using the analogue approach.

Sodium methylparaben (sodium 4-(methoxycarbonyl)phenolate) is the sodium salt of methylparaben (methyl 4-hydroxybenzoate). The substance is highly water soluble (418 g/L), dissociates in aqueous solutions and is hydrolysed to sodium hydroxide and the source substance methylparaben. Based on the assumption that upon oral and dermal administration, sodium methylparaben dissociates and is hydrolysed to methylparaben and sodium hydroxide, it was predicted that after exposure the primary effect is local irritation/corrosion at the site of contact due to sodium hydroxide.

Target and source substance are of low acute toxicity. No systemic or local effects were found up to single doses of 5000 mg/kg bw for sodium methylparaben and 2100 mg/kg bw for methylparaben. A dermal absorption of 80% was calculated for sodium methylparaben using QSAR and the available physico-chemical properties. For methylparaben, the dermal absorption was estimated in an in vitro test to be 84.7% in human skin (Fasano, 2004).

Therefore, it can reasonably be deduced that no higher amounts than tested in the acute oral toxicity study will be systemically available via the intact skin barrier. Inhalation is of no concern for the target as well as the source substance because of the low vapour pressure.

Available data on sodium methylparaben did not show reactive properties under in-vitro test conditions, i. e. Ames test and gene mutation in mammalian cells. Also, by modelling the likelihood of interactions of sodium methylparaben with skin proteins, no structural alerts were found (DR. KNOELL CONSULT, 2012). Data on methylparaben with respect to genetic toxicity in-vivo and skin sensitisation were all negative and are therefore comparable to that of sodium methylparaben. Thus, it is considered that there is no evidence for generation of the chemically reactive metabolites and for interactions with skin proteins for both the target and the source substance.

The results of several repeated dose toxicity studies indicate a low toxicological concern for methylparaben. Methylparaben caused no systemic toxicity and no effects on fertility or developmental toxicity. Moreover, toxicokinetic data have shown that methylparaben is completely absorbed after oral and dermal administration, hydrolysed, conjugated and rapidly excreted in urine. Thus, there is no evidence of accumulation.

As bioavailability and metabolism and therefore mammalian toxicity of sodium methylparaben were considered to be comparable to that of methylparaben, the assessment of systemic toxicity based on analogue approach can be considered as justified.

Several studies have been identified that examine the basic toxicokinetics of Methylparaben:

- Methylparaben was hydrolysed by both liver and skin microsomal/cytosolic fraction of humans and minipigs. The hydrolysis by human esterases was higher than that observed for minipigs.

- High plasma levels and urinary output of free and conjugated p-Hydroxybenzoic acid (metabolite of Methylparaben) in dogs indicate that hydrolysis of the ester linkage and metabolic conjugate constitute the main paths of alteration for Methylparaben. Excretion via urine is almost complete 48 hours after application of 100 mg/kg bw to dogs.

- 1 mg Methylparaben/kg bw/d was applied orally to a dog for one year. The rate of urinary excretion in the dog had increased to such an extent that after 24 hours 96% of the dose was recovered in the urine.

- Methyl p-hydroxybenzoate sodium salt was administered to rabbits (800 mg/kg bw/d) and urine collected for 24 hours was examined for metabolites. After application of a single dose Methylparaben to rabbits the main metabolites found in urine were p-Hydroxybenzoic acid, p-Hydroxyhippuric acid and the ether-type glucuronide.

- Groups of 12 male and 12 female rats received a single dermal administration of 100 mg/kg bw [14C]-labelled Methylparaben. The substance was completely metabolised to 4-Hydroxybenzoic acid. No systemic exposure was detected to Methylparaben 8 h after dermal application.

Taking into account the results of all above mentioned ADME-studies, Methylparaben is considered to be metabolized to p-Hydroxybenzoic acid, which is conjugated to form the glucuronide rapidly and excreted completely within 24 hours after application. There is no tendency for bioaccumulation.

Three dermal absorption studies were performed applying Methylparaben:

- The penetration kinetics and first-pass metabolism of Methylparaben in viable rat (n=10 replicates) and human skin (n=13 replicates) has been determined. The active ingredient was formulated as oil-in-water emulsion at a target concentration of 0.8% and 0.4%. rat and human skin. Penetration was followed using [14C]-labeled active ingredient. The amount of active applied per area skin was approx. 65 µg/cm2and 36 µg/cm2. Following application of a 0.8% Methylparaben emulsion to viable rat and human skin, a greater amount of total radioactivity penetrated human skin (79.36%) compared to rat skin (54.94%). A major portion of the total radioactivity that had penetrated rat skin was metabolised to 4-Hydroxybenzoic acid (53.9%), with a smaller portion (23.8%) accounted for as unmetabolised Methylparaben. By comparison, a lesser portion of the total radioactivity that had penetrated viable human skin had been metabolised to 4-Hydroxybenzoic acid (35.1%), with the majority (60.3%) accounted for as unmetabolised Methylparaben.

- 24 hours after the application on human skin (25 µg/cm2) 33.4% of the applied Methylparaben was absorbed; the surface wash removed unabsorbed Paraben, which was 11.5% of the applied dose. The skin was analysed for Methylparaben and a level of 28.6% was recovered. 24 hours after application to minipig skin, 38.6% of the applied Methylparaben had been absorbed; the skin surface wash contained about 13.4%. 23.9% Methylparaben were extracted from the skin. The metabolite 4-Hydroxybenzoic acid was found in the receptor fluid: 18.1% of the applied amount was found.

- Methylparaben penetrated the dorsal guinea pig skin via non-polarstratum corneumlipid lamella as a rate limiting step for skin penetration. The enhancers tested increase skin penetration of Methylparaben by increasing the fluidity ofstratum corneumlipid lamella, which seems to lead to the increase of diffusion coefficient of the test item.

Methylparaben data:

- log K(p) full thickness (dorsal Guinea pig) skin: -0.9 cm/h

- log (p) lipid depleted (dorsal Guinea pig) skin: -2.25 cm/h

The addition of 1% l-Menthol in 15 % Ethanol increased the permeability coefficient of Methylparaben about 16 times. A similar, though weaker, tendency was observed in the presence of 15 % Ethanol itself without l-Menthol. N-dodecyl-2-pyrrolidone stimulated permeation of relatively hydrophilic Methylparaben.

From these data can be concluded that Methylparaben penetrates human as well as rat and minipig skin. Up to 79 % of the applied amount is absorbed. Up to 35 % of the absorbed substance is metabolised to p-Hydroxybenzoic acid.