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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.

- After a single oral administration of 500 or 1000 mg/kg, Methyl 4-hydroxybenzoate, was rapidly absorbed with mean maximum plasma concentrations observed between 5 and 15 min post dosing. Afterwards, mean concentration-time profiles revealed a multiphasic behaviour with a rapid decline up to 1 hour and a plateau close to the detection limit between 1 and 8 hours. The course of the mean plasma concentrations did not allow extrapolation of the apparent terminal phase and thus, reliable estimation of t1/2 and AUC0-inf was not possible. Fast decline of plasma methyl parabens was accompanied by rapid onset of 4- Hydroxybenzoic acid indicating an efficient and comparable metabolism. In fact, 1 h after dosing mean plasma concentrations of methyl paraben had decreased to less than 10% of the maximum concentration. Furthermore, a substantial portion of the overall exposure was seen within the first hour after dosing.

Taking into account the results of all above mentioned ADME-studies, Methylparaben is considered to be rapidly 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.

 Dermal Absorption

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-polar stratum corneum lipid lamella as a rate limiting step for skin penetration. The enhancers tested increase skin penetration of Methylparaben by increasing the fluidity of stratum corneum lipid 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.