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Endpoint:
basic toxicokinetics
Adequacy of study:
other information

Available data indicate that the oral absorption of DEP is extensive and rapid based on measurement of urinary and faecal excretion. Following oral administration of 14C-DEP to rats and mice (doses not stated), much of the radioactivity from the administered dose (90%) was excreted in the urine within 48 h, with the majority (82%) being eliminated during the first 24 h. Approximately 3% of the radioactivity was found in the faeces over the same period of time (Ioku et al., 1976*; Api, 2001).

Following administration of DEP (10 or 100 mg) by stomach intubation in rats, 85%-93% of the administered dose was excreted in the urine within 7 d as measured by gas chromatography - mass spectroscopy (Kawano, 1980*; IPCS, 2003). For both dose levels, approximately 78% of the administered dose was excreted in urine within 24 h as monoethyl phthalate (MEP) (~70%), phthalic acid (~9%) and parent compound (0.1%-0.4%).

No information is available concerning differences in absorption and bioavailability of orally administered DEP between adult and immature animals or between animals and humans. The oral bioavailability of diethylhexyl phthalate (DEHP) appears to be higher in young rats (Sjöberg et al., 1985). The higher proportion of intestinal tissue in relation to body weight (Younoszai & Ranshaw, 1973), and the relatively higher blood flow through the gastro-intestinal (GI) tract (Varga & Csaky, 1976) have been suggested as the likely factors causing an increased absorption in young animals. Therefore, for the purposes of this assessment, bioavailability of DEP via the oral route is assumed to be 100% for both children and adults.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented and scientifically acceptable, but lacking testing guidelines
Species:
rat
Strain:
Wistar
Sex:
male
Route of administration:
oral: feed
Duration and frequency of treatment / exposure:
34-36 d
Remarks:
Doses / Concentrations:
0, 0.5, 5.0 % in powder diet
No. of animals per sex per dose:
5 males
Control animals:
yes

Body weight, expressed as a percent of each control, decreased gradually (Fig. 1). Organ weights are shown in Table 1. The relative weights of liver, kidney and spleen showed significant increases in the 5% diet group for DBP, whereas the respective substance in the 0.5% diet group elicited almost no change. The testicle weight was markedly decreased in the 5% diet group, but not in the 0.5% diet group. The succinate and pyruvate dehydrogenase activities in liver mitochondria were significantly inhibited with a 5% diet of DBP (Table 2). Such inhibitions were also observed at a 0.5% level of the compound. Glutamate dehydrogenate activity, however, was not affected in any of these groups. These results in mitochondria of DBP-treated rats corresponded well with our previous results).

The inhibitory effects of the compounds on succinate dehydrogenase activity were examined in vitro. DBP significantly inhibited activity in correspondence with its concentration in good accord with our previous results (Table 3). Serum biochemical results are shown in Table 5. The activities of ALP, GOT and GPT increased in rats that received high doses of DBP. Decreased globulin and increased A/G were observed in all groups. Increased CPK activity was found in the DBP group.

Histopathological changes and numbers of rats with such changes are shown in Table 6. The rats treated with DBP revealed abnormal changes in the liver and testicles. In the liver, cytotoxic injury including single cell necrosis, zonal necrosis and degeneration with balloning were observed in many of the rats that received high does of the compounds. Marked spermatogenic damage was seen in the testicles of the 5%-dose group.

Ultrastructural examination of hepatocells was carried out only on the high dose DBP and MBP groups. As shown in Table 7, the effects of DBP treatment were more extensive in increasing peroxisome, lysosome and mitochondria.

Conclusions:
The rats treated with a 5% diet of DBP revealed growth depression, liver enlargement, testicular atrophy, decreased activities of succinate and pyruvate dehydrogenases in liver mitochondria, and abnormal changes in biochemical tests of serum and in histological examinations of the liver and testicle. These adverse effects were also observed in rats fed a 0.5% diet of the compound, although they were less severe.
The changes in hepatocellular ultrastructure were more prominent in rats treated with DBP than in those given MBP. The most striking difference between DBP and MBP was that DBP showed a potent inhibitory effect on succinate dehydrogenase activity in liver mitochondria in vitro, wherease MBP
showed no such effect. This difference was also observed in liver mitochondrial respiration in vitro.
It was suggested that the adverse effects of orally administered DBP at least on the liver may be caused partly by the direct action of intact DBP entering the liver.
Executive summary:

Rats were given a powder diet containing dibutyl phthalate (DBP), monobutyl phthalate (MBP), di-2-ethylhexyl phthalate (DEHP) or phthalic acid (PA) at a level of 0.5 or 5% for 34 to 36 days, respectively. Only the examinations of DBP are documented here, but cf. "overall remarks" for a comparison of the effects of the different substances.

Endpoint:
basic toxicokinetics, other
Remarks:
metabolism
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Species:
other: bacteria
Strain:
other: aeromonas sp., alicaligenes sp., pseudomonas sp.

cf. Executive summary, Figure 1 & Table 2

Executive summary:

This is a short English summary of a full study report written in Japanese:

44 bacterial strains capable of growing on dibutyl phthalate were isolated from soil by enrichment culture, of which 25 strains were Aeromonas sp., 13 strains Alcaligenes sp., and 6 Pseudomonas sp.. Microbiological and physiological properties were investigated for strain no. 12 (Aeromonas sp.), which grew on DBP most abundantly. Cells developed high DBP-oxidizing activity when grown in the medium with ammonium salts as nitrogen source, without addition of iron ion, at around neutral ph. Most phthalate esters tested were assimilated. Cells grown on glucose could constitutively oxidize DBP, phthalate and protocatechuic acid.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Objective of study:
excretion
Species:
other: rat, hamster
Route of administration:
oral: unspecified
Remarks:
Doses / Concentrations:
14C-DBP
doses not reported
Details on excretion:
between 63 % and ≥90 % of the applied dose was excreted in urine within 48 hours
Conclusions:
In studies with rats and hamsters treated orally with 14C-DBP (dose not reported), between 63 % and ≥90 % of the applied dose was excreted in urine within 48 hours.
Executive summary:

Three studies (Williams & Blanchfield 1975, Tanaka et al. 1978, Foster et al. 1983) measured the excretion of 14C-DBP in urine within 48 hours.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Objective of study:
excretion
Species:
rat
Route of administration:
oral: unspecified
Duration and frequency of treatment / exposure:
single dose
Remarks:
Doses / Concentrations:
60 mg 14C-DBP/kg bw/d
No. of animals per sex per dose:
2

Study reports 32.2 % and 56.7 % dose recovery over three days in the bile of two rats with a single oral dose of 60 mg 14C-DBP/kg bw/d. DBP and MBP were the main products in the bile (ratio 1:1). However, it is likely the DBP was reabsorbed from bile and then ultimately excreted in urine, as faecal excretion was low, 1.0–8.2 %.

Conclusions:
Study reported 32.2 % and 56.7 % dose recovery over three days in the bile of two rats with a single oral dose of 60 mg 14C-DBP/kg bw/d.
Executive summary:

The study (Tanaka et al. 1978) suggests, that in addition to elimination through urine, DBP appears to be eliminated in bile. However, it is likely the DBP was reabsorbed from bile and then ultimately excreted in urine.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Objective of study:
excretion
Species:
rat
Sex:
male
Route of administration:
oral: drinking water
Vehicle:
ethanol
Remarks:
50%
Duration and frequency of treatment / exposure:
single dose
Remarks:
Doses / Concentrations:
500 mg 14C-DBP/kg bw/d
Details on dosing and sampling:
bile was collected six hours after exposure

a recovery of 4.5 % of the administered dose in bile was measured

Conclusions:
Study reported a recovery of 4.5 % of the dose in bile collected six hours after a single oral dose of 500 mg 14C-DBP/kg bw/d.
Executive summary:

The study (Kaneshima et al. 1978) measured the concentration of DBP in bile six hours after administration.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Objective of study:
metabolism
Species:
other: rat, baboon, ferret, human

Studies showed hydrolysis of DBP to MBP. The rat liver microsomal fraction demonstrated rapid hydrolysis of DBP to MBP (73 % within two hours). The rate of hydrolysis in the rat GIT was most rapid in the small intestine and slower in the caecum and stomach. Overall phthalate diester hydrolase activity decreased in the order baboon>rat>ferret.

Conclusions:
Studies showed hydrolysis of DBP to MBP.
Executive summary:

Four studies (Lake et al. 1977, Rowland et al. 1977, Tanaka et al. 1978, White et al. 1980) showed and compared hydrolysis of DBP to MPB in different species.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Objective of study:
metabolism
Species:
human
Sex:
male
Route of administration:
oral: unspecified
Duration and frequency of treatment / exposure:
single exposure of D4-DBP and D4-DIBP (in two separate doses)
Remarks:
Doses / Concentrations:
approximately 60 μg/kg D4-DBP and D4-DIBP (in two separate doses)
Details on study design:
The metabolism of DBP and DIBP was investigated in a male human volunteer.

The majority of the dose was excreted (92.2 % DBP and 90.3 % DIBP) in the urine in the first 24 hours, and <1 % was excreted in day 2. For DBP, the simple monoester MBP was the major metabolite detected (84 %). Approximately 8 % was excreted as various oxidised metabolites of DBP. MBP reached peak concentrations 2–4 hours post exposure. The elimination half life of MBP was 2.6 hours, with a longer elimination half time of 2.9 to 6.9 hours for oxidised metabolites.

Executive summary:

The study (Kock HM et al. 2012 ND) in a human volunteer showed excretion of 92.2 % of the administered DBP in the urine in the first 24 hours. The simple monoester MBP was the major metabolite detected (84 %).

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Objective of study:
metabolism
Species:
rat
Details on metabolites:
Study showed only 4.5 % of DBP crossed the intestinal mucosa, with the remainder being hydrolysed by esterases in the mucosal epithelium, before reaching the serosal perfusion solution. Inhibition of esterases reduced DBP hydrolysis, but also significantly reduced DBP absorption, whereas MBP absorption was unaffected.
Executive summary:

The in vitro study (White et al. 1980), using an everted gut sac preparation from rat small intestine, showed, that only 4.5 % of DBP crossed the intestinal mucosa.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Objective of study:
metabolism
Species:
other: rat, hamster
Route of administration:
oral: unspecified
Remarks:
Doses / Concentrations:
2 g DBP/kg bw/d
Details on excretion:
In rats' urine 37.6 % of the dose was recovered as MBP-glucuronide and 14.4 % as unconjugated MBP.
In hamsters' urine 52.5 % of the dose was recovered as MBP-glucuronide and 3.5 % as unconjugated MBP.
Executive summary:

A study (Foster et al. 1983) measured MBP levels in the urine of rats and hamsters, which were treated with DBP.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Objective of study:
metabolism
Species:
rat
Route of administration:
oral: unspecified

After administering DBP orally to rats, MBP, MBP-glucuronide, various ω- and ω-1-oxidation products of MBP (more polar ketones and carboxylates) and a small amount of phthalic acid were detected.

Executive summary:

Four studies (Albro & Moore 1974, Williams & Blanchfield, 1975, Tanaka et al. 1978, Foster et al. 1983) in the metabolism effects on rats detected MBP, MBP-glucuronide, various ω- and ω-1 -oxidation products of MBP and a small amount of phthalic acid.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Species:
rat
Route of administration:
oral: unspecified
Remarks:
Doses / Concentrations:
60 mg 14C-DBP/kg bw/d (in DMSO)
Details on study design:
study determined retention in 14 different tissues

At 24 hours after administration, no retention was seen in brain, heart, lung, spleen, testicles, prostate or thymus and only low amounts were detected in the following tissues: liver (0.06 %), kidneys (0.02 %), muscle (0.3 %), adipose tissue (0.7 %), intestines (1.53 %), stomach (0.01 %) and blood (0.02 %).

Conclusions:
At 24 hours after administration only low amounts were detected in the following tissues: liver (0.06 %), kidneys (0.02 %), muscle (0.3 %), adipose tissue (0.7 %), intestines (1.53 %), stomach (0.01 %) and blood (0.02 %).
Executive summary:

The study (Tanake et al. 1978) detected the highest radioactivity in intestines (1.53%). No retention was seen in brain, heart, lung, spleen, testicles, prostate or thymus.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Species:
rat
Route of administration:
inhalation
Duration and frequency of treatment / exposure:
daily inhalation exposure to DBP at 50 mg/m3 and 0.5 mg/m3 for three and six months
Remarks:
Doses / Concentrations:
0.5, 50 mg DBP/m3
Details on study design:
Study to measure organ distribution of DBP.
No metabolites were measured in this study.
Details on metabolites:
not measured

The highest concentrations of DBP at both dose levels were found in the brain. At the higher dose, the maximum levels of DBP detected in the brain were 0.42–0.68 mg/kg and 0.54–1.46 mg/kg, after three and six months of exposure respectively. Accumulation in other organs was less marked.

Executive summary:

The study Kawano (1980) showed increasing accumulation of DBP in organs with extended duration of treatment.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Route of administration:
oral: unspecified
Duration and frequency of treatment / exposure:
single dose on gestation day 14
Remarks:
Doses / Concentrations:
500, 1500 mg 14C-DBP/kg bw/d
Details on study design:
placental transfer study
Maternal and foetal tissues were collected at intervals from 0.5 hours to 48 hours.
Details on distribution in tissues:
Radioactivity in embryonic tissues was <0.12–0.15 % of the dose. Radioactivity in the placenta and embryo was less than or equal to one-third of that in maternal plasma. No accumulation of radioactivity was observed in maternal or embryonic tissues.
Details on metabolites:
DBP and the metabolites MBP and MBP-glucuronide were shown to rapidly transfer to embryonic tissues at levels that were consistently lower than those in maternal plasma.

Most of the radioactivity recovered in maternal plasma, placenta and embryo was attributed to MBP with intact DBP present at low levels.

Executive summary:

The study (Saillenfait et al. 1998) showed that the accumulation of radioactivity in the placenta and embryo was lower than in the maternal plasma.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Route of administration:
oral: unspecified
Duration and frequency of treatment / exposure:
single dose group: GD 19
repeated dose groups: GD 12-19
Remarks:
Doses / Concentrations:
single dose: 500 mg DBP/kg bw/d
repeated dose: 50, 100, 500 mg DBP/kg bw/d
Details on study design:
Study monitored distribution of MBP in pregnant SD rats.
Tissue distribution of MBP and MBP-glucuronide were monitored by liquid chromatography/mass spectrometry in maternal and foetal plasma, placenta and amniotic fluid.

MBP in maternal plasma, placenta, and foetal plasma was mostly eliminated after 24 hours. Both placenta and foetal serum kinetics closely followed the maternal plasma, though the foetal plasma showed a slight delay in the time to reach peak concentration. Amniotic fluid MBP levels were not linearly correlated with either the maternal or foetal plasma when examined across doses. Maternal and foetal plasma MBP levels were consistently lower at repeated doses compared with a single dose, suggesting that metabolism of DBP was induced with multiple exposures. MBP concentrations in the amniotic fluid were also reduced with repeated doses of 500 g/kg DBP, compared with the single administration.

Conclusions:
Maternal and foetal plasma MBP levels were consistently lower at repeated doses compared with a single dose, suggesting that metabolism of DBP was induced with multiple exposures. MBP concentrations in the amniotic fluid were also reduced with repeated doses of 500 g/kg DBP, compared with the single administration.
Executive summary:

The study (Clewell et al. 2009 ND) showed that maternal and foetal plasma MBP levels, of rats treated with DBP, were consistently lower at repeated doses compared with a single dose.

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Species:
other: rat, hamster, human
Route of administration:
oral: unspecified

DBP is readily absorbed from the gastrointestinal tract (GIT). In studies with rats and hamsters treated orally with 14C-DBP (dose not reported), between 63 % and ≥90 % of the applied dose was excreted in urine within 48 hours (Williams & Blanchfield, 1975*; Tanaka et al. 1978*; Foster et al. 1983*). Faecal excretion was low (1.0–8.2 %) (Tanaka et al. 1978*).

Tomita et al. (1977*) reported oral absorption of DBP in humans after detecting increases (cf. controls) in blood levels in 13 individuals who had ingested food contaminated with DBP from plastic packaging.

Conclusions:
DBP is readily absorbed from the gastrointestinal tract (GIT).
Executive summary:

Five studies report oral absorption of DBP in different species (rats, hamsters, humans).

Endpoint:
basic toxicokinetics
Adequacy of study:
other information
Species:
rat
Strain:
Wistar
Sex:
male
Route of administration:
oral: feed
Vehicle:
corn oil
Remarks:
Doses / Concentrations:
0.27, 2.3 g 14C-DBP/kg bw/d
Details on distribution in tissues:
Tissue distribution was similar at both dose levels. Less than 0.01 % radioactivity was detected in all tissues after 48 hours.

The highest radioactivity was recorded in the kidneys (0.66 %) and the lowest was recorded in the brain (0.03 %), four hours after administration. Radioactivity was detected at 0.4 % of the dose in the blood, at both dose levels, after 24 hours.

Executive summary:

The study (Williams & Blanchfield 1975) recorded the highest radioactivity in the kidneys (0.66 %) and the lowest was recorded in the brain (0.03 %), four hours after administration. Less than 0.01 % was detected in all tissues after 48 hours.

Endpoint:
dermal absorption
Adequacy of study:
other information
Species:
human
Strain:
other: Caucasian
Sex:
male
Vehicle:
other: basic cream
Duration of exposure:
5 days
Doses:
2% (= approximately 800 mg) DEP, 2% DBP and 2% butyl paraben
No. of animals per group:
26

Two hours after the first cream application containing approximately 800 mg DEP, serum concentrations of MEP peaked at 1000 µg/L (corresponding to 6.9 mg or ~10% of absorbed DEP) and decreased to 23 µg/L after 24 h just before the second application, but did not reach the baseline levels observed in the first week. Average daily recovery of DEP excreted in urine as MEP was 5.8%

Executive summary:

The study (Janjua et al. 2007) showed that DEP is dermal absorbed, but most of it is segregated within 24 hours.

Endpoint:
dermal absorption
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Conclusions:
DBP absorption via the dermal route in humans is low .
Dermal absorption in rat is 40 times higher in comparison to humans, therefore studies in rats about dermal DBP absorption are not representative for human skin.
Executive summary:

Absorption via the dermal route and subsequent elimination was assessed after application of 43.7 mg/kg 14C-DBP in ethanol (with occlusion) to the clipped skin of male F344 rats, followed by measurements of the excreted 14C radiolabel. Over seven days, DBP was excreted in urine and faeces at a nearly constant rate of approximately 10–12 % of the applied dose each day. Around one third of the applied dose remained at the site of application (Elsisi et al. 1989). In a comparative in vitro study, Scott et al. (1987) demonstrated that the rate of dermal absorption for DBP is about 40 times greater in rat than in human epidermal skin preparations (93.35 μg/cm2/h and 2.40 μg/cm2/h, respectively). More recently, Janjua et al. (2007 ND, 2008 ND) examined systemic uptake and elimination of DBP after dermal application in human volunteers. About 40 g of a standard cosmetic lotion formulation without (during control week) or with 2 % DBP (during treatment week) was applied to the whole body of 26 adult males for five consecutive days. The volunteers did not use any phthalate containing cosmetics for three weeks before the treatment week. Serum and urine concentrations of the primary metabolite, monobutyl phthalate (MBP), were measured. Urine was collected as individual samples at different time points during the first day of the treatment week and as 24-hour pools on all consecutive days. Results demonstrated increases in MBP in serum and urine within a few hours of application. An average of 1.82 % (range 0.11–5.94 %) of the applied DBP dose was recovered in urine as MBP during the treatment week. Taking into consideration the studies in rodents that demonstrate absence of significant bioaccumulation of DBP in any organs or tissues, the studies by Janjua et al. suggest that DBP absorption via the dermal route in humans under conditions of usual cosmetic application is low. A study with hairless guinea pigs (Doan et al. 2010 ND) that compared in vivo and in vitro skin absorption of DBP from an oil-in-water emulsion, found that in vivo, 62.0 % ±2.0 % (mean of three animals ±SEM) of the applied dose (AD) was systematically absorbed. Most of this (60.4 ±1.8 %AD) was excreted in the urine and less than 2 % was found in other tissues (ovaries, kidneys, liver). The amount of applied dose retained in the skin after 24 hours was 2.2 ±0.3 % AD; 7.4 ±2.3 % AD was trapped as volatile material in the first hour after dosing. The amount of DBP absorbed in vivo after 24 hours closely agreed with the amount of DBP found in the receptor fluid in vitro after 72 hours, suggesting that in vitro DBP is a lipophilic chemical that can initially form a reservoir in skin, and can slowly diffuse out of the skin into the receptor fluid. The relative permeability of human and guinea pig skin for DBP from this particular oil-in-water emulsion has not been compared.

Endpoint:
dermal absorption
Adequacy of study:
other information
Species:
rat
Strain:
Fischer 344
Duration of exposure:
7 days
Doses:
43.7 mg/kg bw/d without occlusion, or 157 μmol/kg bw/d with occlusion

Low accumulation in adipose tissue (0.41 %), skin (1.4 %), muscle (1.1 %) and all other tissues <0.5 %.

A third of the applied dose remained at the site of application.

Executive summary:

The study (Elsisi et al. 1989) showed low accumulation in adipose tissue (0.41 %), skin (1.4 %), muscle (1.1 %) and all other tissues <0.5 %.

Description of key information

Dibutylphthalate is rapidly absorbed and excreted after oral administration as was demonstratedin studies in laboratory animals. Up to more than 90% of oral doses given to rats or hamsters wasexcreted in urine within 24-48 hours. Fecal excretion is low (1.0-8.2%).

Also in man oral absorption of DBP takes place

After dermal exposure of rats to DBP ca. 60% of the dose was excreted in urine within 7 days. Infeces ca. 12% of the dose was found. Anin vitrostudy revealed slower absorption of DBP by thehuman skin (2.40μg/cm2/hr) than by the rat skin (93.35μg/cm2/hr).

Data on absorption after exposure by inhalation are not available.

A substantial fraction of DBP is initially excreted in the bile and subsequently enters theenterohepatic circulation.

No significant accumulation in tissues was observed in laboratory animals after oral as well asdermal exposure; limited inhalation data revealed an indication for some accumulation in tissues.

The major part of DBP is hydrolysed to mono-n-butyl phthalate (MBP) and the correspondingalcohol prior to absorption by the small intestines, but hydrolysis can also occur in liver andkidneys. The metabolites that occur in urine are MBP, MBP-glucuronide, variousω- andω-1-oxidation products of MBP (more polar ketones, carboxylates) and a small amount of freephthalic acid. Species differences in the excretion of MBP and its glucuronide were observed;rats excreted a larger proportion unconjugated MBP in urine than hamsters.

There are no data on biotransformation after dermal exposure and exposure by inhalation.

Transplacental transfer of DBP and its metabolites was demonstrated in an oral study with14C-labelled DBP in rats. Radioactivity in embryonic tissues contained less than 0.12-0.15% ofthe administered dose. MBP accounted for most of the radioactivity in maternal plasma, placenta and embryo. Unchanged DBP was found in only small amounts. No accumulation ofradioactivity was seen in maternal or embryonic tissues.(1)

(1)

European Union Risk Assessment Report dibutyl phthalate, Volume 29, pp. 14 -15 (2003)

Editors: B. G. Hansen, S.J. Munn, R. A/Ianou, F. Berthault, J. de Bruin, M. Luotamo, C. Musset, S. Pakalin, G. Pellegrini, S. Scheen S. Vegro.

Office for Official Publications of the European Communities, ISBN 92—894—1276—3

In laboratory animals (rats and hamsters), DBP is rapidly absorbed and excreted after oral administration, with ≥90 % excreted in the urine within 24–48 hours. Faecal excretion is low (1.0–8.2 %). DBP is also excreted in the bile and consequently enters the enterohepatic circulation (Williams & Blanchfield 1975*; Tanaka et al. 1978*; Foster et al. 1983*). Limited data in humans also indicate that DBP is absorbed after oral exposure (Tanaka et al. 1978*). Therefore, the bioavailability of DBP via the oral route in humans is considered to be 100 % for both adults and children.

Absorption via the dermal route in rats was estimated at around 10–12 % per day over seven days (Elsisi et al. 1989). In vitro, absorption of DBP through epidermal rat skin preparations is about 40 times greater than through human skin preparations (Scott et al. 1987). These data indicate that dermal absorption of DBP in humans is not likely to exceed 2 %. However, this might vary depending on the conditions and formulation in which DBP is applied to the skin. Recent human studies with dermal application of cosmetic lotion formulations containing DBP are consistent with the estimated 2 % dermal absorption of DBP via the human skin. However, significant interindividual and daily variations were observed, with a maximum dermal absorption in volunteers corresponding to approximately 6 % of the applied DBP dose (Janjua et al. 2007, 2008). Based on all data available for DBP, a 5 % bioavailability for DBP is estimated for humans through dermal exposure.

There are limited data regarding DBP absorption via the inhalation route. One inhalation study suggests some accumulation in tissues following inhalation exposure in rats, indicating that DBP might be absorbed via the inhalation route (Kawano et al 1980a*). However, in this study only DBP (and not metabolites) was measured. In the absence of sufficient data, a default of 100 % absorption via the inhalation route is considered appropriate for DBP for risk characterisation.

No significant accumulation of DBP in tissues was seen in laboratory animals after oral and dermal exposure.

DBP is mostly hydrolysed to MBP before absorption by the small intestines. DBP hydrolysis can also occur in liver and kidneys. Metabolites in urine include MBP, MBP-glucuronide, various ω- and ω-1-oxidation products of MBP (more polar ketones and carboxylates) and a small amount of phthalic acid. No data on biotransformation after dermal or inhalation exposure are available.

Placental transfer studies revealed that DBP and its metabolites, MBP and MBP-glucuronide, are rapidly transferred to embryonic tissues without significant accumulation in the placenta or foetal tissues (Saillenfait et al. 1998*; Clewell et al. 2009).(2)

(2) Priority Existing Chemical Assessement Report No. 36 - Dibutyl phthalate; Australian Government, Department of Health; National industrial chemicals notification and assessment scheme, GPO Box 58, Sydney NSW2001, Australia; ISBN: 978 -0 -9874434 -4 -1, pp. 81f.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
5

Additional information