Oral Propylparaben Administration to Juvenile Male Wistar Rats Did Not Induce Toxicity in Reproductive Organs

Abstract

Parabens are in widespread use as preservatives in drugs. In the late 1990 s, concerns were raised about their capacity to disrupt endocrine function based on in vitro data and in vivo uterotrophic tests. Studies in juvenile male rats provided conflicting results on pospubertal sperm production. In an exploratory pharmacokinetic study, Wistar male rats received a single dose of propylparaben (PP) at 3, 10, 100, or 1000 mg/kg, orally on postnatal day (PND) 31. Plasma PP concentrations were quantifiable up 8h after dosing with a mean T max value of 15 min. Distribution was 4.8 l/kg, the plasma elimination half-life was 47 min, and clearance was 4.20 (l/h)/kg at 10mg/kg. A sulfoconjugated metabolite was detected. In the juvenile toxicology study, PP was orally administered by gavage to 20 Wistar male rats at doses of 3, 10, 100, or 1000 mg/kg/day in 1% hydroxyethylcellulose for 8 weeks starting on PND21. A first subgroup of 10 males/dose was necropsied immediately after the 8-week exposure period; a second subgroup of 10 males/dose was necropsied after a 26-week washout period. Blood samples were taken from additional satellite animals after dosing on PND21 and PND77 for toxicokinetic analysis. There was no evidence of an effect of PP on the weight of the male reproductive organs, epididymal sperm parameters, hormone levels, or histopathology. The dose of 1000 mg/kg/day was the no-observed adverse effect level, corresponding to a maximum plasma concentration of 12,030 ng/ml and exposure to 47 760 ng · h/ml (AUC0-8 h) at the end of the treatment.

A case study on quantitative in vitro to in vivo extrapolation for environmental esters: Methyl-, propyl- and butylparaben

“…Aubert et al (2012) (Aubert et al, 2012) reflecting poor absorption through the 77 dermal route. Gazin et al (2013) found no measureable levels of PP 78 in plasma of rats 4 h post a single oral bolus up to 1000 mg/kg and 79 kinetics were non-linear at doses above 10 mg/kg. The only controlled dosing study in humans was a 5 day dermal 178 exposure study reported Q6 by Janjua et al (2008).…”

“…In vitro studies of metabo-58 lism in microsomal systems from various tissues including liver, 59 intestine and skin also reported that parabens are rapidly 60 hydrolyzed to 4-hydroxybenzoic acid (pHBA) in mammals (Abbas 61 et al, 2010;Jewell et al, 2007a,b;Ozaki et al, 2013) by 62 carboxylesterases. Parabens are also directly conjugated with 63 glucuronide, sulfate or glycine prior to excretion (Abbas et al,64 2010; Gazin et al, 2013;Ye et al, 2006Ye et al, , 2009. There are notable 65 differences in the predominant conjugate seen between rats and 66 humans.…”

“…There are notable 65 differences in the predominant conjugate seen between rats and 66 humans. In the rat, sulfation predominates (Gazin et al, 2013), 67 while in the human, nearly equal amounts of sulfate and 68 glucuronide conjugates were measured in human spot urine 69 samples (Ye et al, 2006). Aubert et al (2012) (Aubert et al, 2012) reflecting poor absorption through the 77 dermal route.…”

Regulatory risk assessments

“…9 Parabens are rapidly hydrolysed in vivo by carboxylesterases (mainly in skin, plasma and liver) to PHBA, a common metabolite for all parabens, which is nontoxic, ubiquitous in human nutrition and possesses no or negligible oestrogenic activity. 18 Concerns over potential carcinogenic activity of parabens have been consistently ruled out in the various expert reviews cited above. Kinetic investigations on several parabens have been undertaken in rats, 16,19 and the results are summarized in the most recent SCCS review, as follows:…”

“…In their most recent review in 2013, 17 SCCS evaluated Gazin et al's 8-week oral toxicity study (PND 21-77) on PP 18 with its associated TK data. PP was rapidly absorbed; for total PP (free and conjugated), the maximum plasma concentrations were generally observed 0.25-0.5 h after dosing.…”