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Description of key information

Short description of key information on bioaccumulation potential result: 
In rats, BBP is readily absorbed from the gastrointestinal tract, but less so through the skin. Data on its absorption after inhalation exposure are lacking. BBP is metabolized to monobutyl phthalate and monobenzyl phthalate, the main urinary metabolite being monobutyl phthalate in rats and monobenzyl phthalate in humans. There is no evidence of tissue accumulation.
Short description of key information on absorption rate:
Two reliable dermal absorption studies have been identified. In an in vivo rat study, the application of BBP at 49 mg/kg bw (or 7.7 mg/cm2) for 7 days resulted in 35% of the dose being absorbed over this period (i.e. 5% per day), while an in vitro human study demonstrated just 0.2% absorption after an 8-hour application of 100 ul/cm2 to skin taken from a human cadaver. The EU RAR suggests that 5% would be a worst-case estimate of dermal absorption.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
5

Additional information

In a reliable study in human volunteers, groups of 8 individuals were given 0, 253 or 506 µg of radiolabelled benzylbutylphthalate (deuterated, d4-BBP), which was spiked into margarine and spread on toast as breakfast. During the day prior to dosing, the day of dosing and days 2 and 6 post-dosing, 24-hour urine samples were collected and analysed for d4-phthalate monoester metabolites, monobenzylphthalate (MBeP) and monobutylphthalate (MBuP). In the first 24-hours post-dosing, the mean amounts of d4-MBeP detected in the urine were 140 and 323 µg (with relative standard deviations of 39% and 26%) in the low- and high-dose groups, respectively, representing excretion yields (conversion rates) of 67 and 78%, respectively, on a molar basis. At the high dose, 20 µg d4-MBuP (relative standard deviation 59%) was also excreted, representing a conversion rate of 6%, but at the low dose it was undetectable. Neither metabolite was detectable in urine collected during days 2 and 6 post-dosing. Thus, in this reliable human study, MBeP was identified as the main metabolite and MBuP as a secondary metabolite after a single oral administration of BBP to groups of 8 volunteers at around 3.6 or 7.2 µg/kg bw. Both monoesters were eliminated rapidly during the first 24 hours after dosing (Anderson et al., 2001).

 

In a reliable excretion study in rats, groups of three males were given a single oral gavage dose of14C-BBP at 2, 20, 200 or 2000 mg/kg bw. Urine and faeces were collected daily, and radioactivity levels were determined by liquid scintillation counting. Urine samples collected at 24 hours were analysed for monophthalate and monophthalate-glucuronide.

For all dose groups, 75-86% of the administered dose was excreted in the urine and faeces over the first 24 hours, and 92-98% after 96 hours. At 96 hours, the proportions of the dose excreted in the urine and faeces were 71-80% and 18-23% respectively at 2-200 mg/kg bw, which contrasted with 22 and 72% respectively at 2000 mg/kg bw. The "identified" urinary metabolites were monophthalate and monophthalate-glucuronide, the respective levels of which (as a percentage of dose) were 27 and 21% at 2 mg/kg bw, 22 and 20% at 20 mg/kg bw, 42 and 14% at 200 mg/kg bw and 10 and 2% at 2000 mg/kg bw. The remaining metabolies were unidentified. This reliable study demonstrated that, when rats were given a single oral dose of14C-BBP, radioactivity was eliminated primarily in the urine at doses of 2-200 mg/kg bw and primarily in the faeces at 2000 mg/kg bw. After 24 hours, 75-86% of the dose had been eliminated and 92-98% after 4 days. The major urinary metabolites were monophthalate and monophthalate glucuronide (Eigenberg et al., 1986).

 

The same group of investigators also conducted excretion studies in which two groups of three male rats were given a single intravenous injection of14C-BBP at 20 mg/kg bw. In one group, radioactive metabolites were quantified in bile and urine 4 hours after dosing. In the second group, urine and faeces were collected over the 24 hours following dosing and excretion of radioactivity was evaluated. At 4 hours after dosing, 55% of the dose (as14C) was excreted into the bile and 34% in the urine. There was no parent compound in the bile, but the metabolites MBuP, MBeP and their glucuronides were present. Thus, 26% of the administered dose was present in the bile as MBuP-glucuronide, 13% as MBeP-glucuronide, 1.1% as free MBuP and 0.9% as free MBeP, with 14% as unidentified metabolites. In the urine at the 4-hour timepoint, 15% of the administered dose was present as MBuP-glucuronide, 2% as MBeP-glucuronide, 1.8% as free MBuP and 0.3% as free MBeP. The total proportions of the two main metabolites in bile and urine (as a percentage of the administered dose) were 44% MBuP and 16% MBeP. Over the 24 hours immediately after dosing, 94% of the dose was excreted in the urine and faeces, in the proportions 74% and 20% respectively. The "identified" urinary metabolites were monophthalate and monophthalate-glucuronide, the respective levels of which (as a percentage of dose) were 42 and 11%. The remaining metabolites were unidentified. This reliable study showed that, when rats were given a single intravenous injection of14C-BBP at 20 mg/kg bw, metabolism was rapid, with bile as the major route of excretion of metabolites after 4 hours. Radioactivity detected in the bile and urine 4 hours after dosing was present as MBuP (44%) and MBeP (16%), both of which existed as free and conjugated forms. After 24 hours, 94% of the dose had been eliminated, mainly in the urine (Eigenberg et al. 1986).

 

A study was carried out to determine the metabolites of BBP in rat urine after oral exposure. Two male rats were dosed for 3 days with 1125 mg BBP/kg bw/day, and the combined urine samples were analysed for metabolites. The two main metabolites, MBuP and MBeP, were then given orally at 800 and 925 mg/kg bw/day respectively, to groups of five male rats for 7 days. Both free and conjugated metabolites were detected in the urine, the main metabolites being MBuP and MBeP at a ratio of about 5:3 (Mikuriya et al., 1988).

 

There is a lack of data on the extent of systemic availability of BBP following inhalation exposure.

 

In any risk characterization, 100% absorption can be assumed for inhalation exposure and 70 -80% for oral exposure, whereas a lower absorption level should be assumed for dermal exposure (see dermal absorption section).

Discussion on absorption rate:

In a reliable dermal absorption study,14C-labelled BBP was applied to the shaved skin of three male rats at a dose of 49 mg/kg bw on an area of 1.3 cm2. The application was semi-occluded for 7 days during which time urine and faeces were collected. At study termination, samples of a number of tissues were taken. Radioactivity was determined in all these tissues and excreta. The proportion of the administered dose found in the tissues and excreta after 7 days was 30% in urine and faeces, 4.6% in muscle, <0.5% in brain, spinal cord and testis, 0.17% in adipose tissue, and 0.08% in skin distant from the application site, making a total of about 35% (i.e. 5% per day). Total recovery (including site of application and covering) was 86% (Elsisi et al., 1989).

 

The potential dermal penetration and absorption of BBP through human skin has been determined using an in vitro dermal penetration study, performed according to OECD Guideline 428 (and GLP).14C-labelled test material was applied at a rate of 100 ul/cm2for 8 hours in a static cell diffusion system, and the distribution of radiolabelled material within the test system (from receptor fluid, skin wash, donor chamber, stratum corneum and residual skin tissue) was determined. The mean overall recovery was 96.4% of the applied dose, with the vast majority remaining in test solution or washed off the skin; only 0.582% was recovered from the stratum corneum using tape strips, and an even smaller percentage (0.197%) remained absorbed in the skin. There was no detectable penetration through the skin. The overall skin absorption of BBP (0.197%) is likely to be an overestimate, as the study was designed to measure skin penetration under conservative conditions (Tedesco, 2006).  

The in vivo rat study indicates an absorption rate of 5% per day, while the in vitro human study found just 0.2% absorption over an 8 -hour period. The EU RAR suggests that 5% would be a worst-case estimate of dermal absorption, as the experimental exposure conditions in the rat study are not representative of normal exposure.