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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Publication

Data source

Reference Type:
Pharmacokinetic profile of propyl paraben in humans after oral administration
Mi-Yeon Shina, Chorong Shina, Jeong Weon Choia, Jangwoo Leea, Seungho Leeb,
Sungkyoon Kima

Materials and methods

Objective of study:

Test material

Specific details on test material used for the study:
For this study, n-propyl 4-hydroxybenzoate-2,3,5,6-d4 (PP-d4,
98.8%) and p-hydroxybenzoic-2,3,5,6-d4 (pHBA-d4, 99%) were purchased
from CDN Isotopes Inc. (Point-Claire, Quebec, Canada). Because
deuterated p-hydroxyhippuric acid was not commercially available, phydroxyhippuric
acid (pHHA,>99%) was obtained from Bachem
(Torrance, CA, USA). 13C6-propyl-4-hydroxybenzoate (13C6-PP) was
purchased from Sigma-Aldrich (St. Louis, MO, USA) and used as an
internal standard.

Administration / exposure

Details on study design:
Twelve healthy adult volunteers were recruited for this study. Only male volunteers were chosen to exclude potential variations according to sex. All were non-smokers. Their average age was 27.5 ± 6.2 years. Their average height, body weight, and BMI were 174.8 ± 4.2 cm,72.6 ± 10.2 kg, and 22.7 ± 3.2 kg/m2, respectively. The 12 volunteers were divided into two groups, consisting of seven and five volunteers who participated in the experiment in 2013 (study I) and 2015 (study II), respectively. For dosage, isotope-labeled analog (d4-labeled) PP was used due to the known background exposure to parabens.The administered dose was set to be below the acceptable daily intake (ADI) of 10 mg/kg b∙w/day for the sum of MP and EP, instead of PP, because PP is not included in the combined ADI (JECFA, 2007). The dose was selected as 2.5 mg/kg b∙w by dividing ADI by major four parabens.
In addition, the dose at which free PP could be detected in blood was also considered. Based on the concentration of free PP in study I, the dose was reduced to 0.6 mg/kg b∙w in study II. On the day of the experiment, volunteers were housed and monitored in a clinical room. They were provided with a small snack ball that contained 0.1 mL of the deuterated propyl paraben solution dissolved in ethanol. All volunteers were administered the snack once. In study I, blood samples were collected in serum-separating tubes before administration (T0) and at 0.25, 0.5, 1, 2, 4, 6, and 8 h postadministration. In addition, urine samples were also collected at T0 and at 0.5, 1, 2, 4, 6, 8, 12, and 24 h post-administration. Based on the results of study I, we modified the blood sampling time points to T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h post-administration in study II. For urine sampling, additional time points (3, 48, 72 h) were monitored. The volume of each urine sample was recorded, and all samples were stored at −70 °C until analysis. Both experiments were approved by the Seoul National University Institutional Review Board (IRB No. 27-2013-0520 and 1508/001-007).

Results and discussion

Applicant's summary and conclusion

The results of this study suggest that PP is rapidly absorbed and systemically distributed in humans after oral ingestion. Furthermore, most
PP is likely to be metabolized prior to excretion, and PP is rarely present in its free form in the human body. With regard to metabolism, the
hydrolysates pHBA and pHHA are formed and eliminated faster than the conjugates. The Fue for total PP (free plus conjugates) and the total
range of investigated substances, including metabolites, were 8.6% and 38.7%, respectively.
Executive summary:

Parabens are commonly used as antimicrobial preservatives in consumer products. Although pharmacokinetic studies on

parabens have been conducted in animals, limited information exists on their pharmacokinetic profiles in humans.

In the present study, the pharmacokinetic characteristics of propyl paraben (PP) in humans

following a single oral administration of 0.6 mg/kg bw of deuterium labeled-PP was investigated. furthermore another experiment was conducted with similar design but different exposure amount (2.5 mg/kg bw) to verify the validity of the model to be developed. Blood and urine were collected at several intervals over the course of 48 h to measure levels of PP and its metabolites (conjugates and hydrolysates) in 12 male volunteers. The unconjugated parent compound (free PP), glucuronide and sulfate conjugates, p-hydroxybenzoic acid, and p-hydroxyhippuric acid were measured using HPLC-MS/MS.

It was found that PP was rapidly absorbed via ingestion within 2 h and quickly eliminated

(terminal half-life, 2.9 h). The fraction of administered dose excreted in the urine was 0.05% for free PP, 8.6% for

total PP (free + conjugates), 23.2% for p-hydroxyhippuric acid, and 7.0% for p-hydroxybenzoic acid.

The present pharmacokinetic model provides insights into the kinetic properties of the disposition of PP

and its metabolites in humans, and it can be used for risk assessment with biomonitoring of PP.