Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Significantly aobsorbed following oral exposure, less so following dermal exposure. Metabolised to the mono-ester and rapidly excreted, mainly via urine. Low potential for accumulation within tissues.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10

Additional information

Absorption

Oral

Ioku et.al. (Yakuri To Chiro 4: 510-514, 1976) report that approximately 90% of radioactivity from an administered dose was excreted in the urine within 48 hours following oral administration of14C-DEP to rats and mice, with the majority (82%) being eliminated during the first 24 hours. Approximately 3% of the radioactivity was found in the faeces over the same period of time. This suggests that absorption of DEP is extensive and rapid following oral administration.

Kawano (Japanese Journal for Hygiene 35(4): 693-701, 1980) reports85% - 93% of an oral gavage dose of 10 or 100 mg to rats being excreted in the urine within 7 days. Approximately 78% of the administered dose was excreted in urine within 24 hours, approximately 70% being in the form of the mono-ester, 9% as phthalic acid and 0.1%-0.4% as the parent di-ester.

Dermal

The dermal absorption of DEP has been examined in-vivo in the rat byElsisi et.al. (Fundamental and Applied Toxicology 12: 70-77 1989).14C-DEP was applied to male rat skin at 5-8 mg/cm2under occlusion.Urine and faeces were collected every 24 hours and the amount of radioactivity14Cexcreted was taken as an index of the percutaneous absorption. Excretion in urine & faeces after 24 hours was 24% & 1%, respectively and cumulative excretion was 50% in 7 days. After 7 days 34% of the administered dose remained on the application site. Amounts detected in tissues were 0.0 -0.5% of the administered dose.

Mint et.al. report investigations of percutaneous absorption using in vitro techniques with flow-through diffusion cells and shaved full-thickness skin from male Fischer 344 rats and human breast skin ( Toxicology in vitro 8: 251-256, 1994. Neat DEP (16.3–20.6 mg/cm2) was applied to the epidermal surface of the skin, which was then either left uncovered (unoccluded) or covered (occluded). Dermal absorption of14C-DEP through male rat dorsal skin was approximately 35.9%,ranging from 26.4 ± 3.3% (mean ± SD, n = 4) to 38.9 ± 0.6% (mean ± SD, n = 5). Absorption across human breast skin was approximately 3.9% after 72 hours under occlusive conditions,ranging from 1.6 ± 1.2% (mean ± SD, n = 3) to 8.7 ± 3.9% (mean ± SD, n = 6) at 72 hours. Occlusion of the skin did not significantly alter the percutaneous absorption of DEP through rat or human skin.

A number of healthy male Caucasians were given a whole body topical application (5 d/week) of 2 mg/cm2basic cream without (week 1–control week) and with (week 2) DEP, dibutyl phthalate (DBP), and butyl paraben at 2% w/w each as part of a 2-week single-blinded study (Environmental Science and Technology 41: 5564-5570, 2007 and International Journal of Andrology 31: 118-130, 2008). Serum concentrations of the mono-ester metabolite, MEP, peaked at 1000 µg/L (corresponding to approximately 10% of absorbed DEP) 2 hours after the first cream application containing approximately 800 mg DEP, and decreased to 23 µg/L after 24 hours just before the second application. Daily recovery of DEP excreted in urine as MEP averaged 5.8%.

 

DEP therefore appears to be well absorbed via the skin. Human studies indicate a lower dermal absorption than that seen in rats, with approximately 10% and 5.8% of dermally applied DEP found in serum and urine, respectively within 24 hours. A dermal bioavailability for DEP of 10% in humans may be assumed.

Distribution

Ioku et.al. (Yakuri To Chiro 4: 510-514, 1976) report that, following oral administration of14C-DEP to rats and mice, the radioactivity was widely distributed with the highest concentrations observed in kidney and liver, followed by blood, spleen and adipose tissue. Highest levels were noted within 20 minutes, followed by a rapid decrease to only trace amounts after 24 hours.

Little radioactivity was found in the tissues 7 days following application of a single dose of DEP to the skin of the male rat. The amounts of radioactivity in the adipose tissue, muscle, skin, brain, lung, liver, spleen, small intestine, kidney, testis, spinal cord and blood were each less than 0.5% of the dose(Fundamental and Applied Toxicology 12: 70-77 1989).

 

Metabolism

The mono-ester, MEP, was the major urinary metabolite identified following oral dosing of rats and mice (Yakuri To Chiro 4: 510-514, 1976). Phthalic acid was identified as a minor secondary metabolite.

In another study, approximately 70% of the dose administered by stomach intubation in rats was excreted in urine within 24 hours as the mono-ester, MEP (Japanese Journal for Hygiene 35(4): 693-701, 1980). Hydrolysis of the di-ester to the monoester in the skin has also demonstrated in vitro for both rats and humans by Hotchkiss and Mint (Journal of Investigative Dermatology 102: 647, 1994).

 

Excretion

DEP appears to be rapidly eliminated with the urine appears to be the major route of DEP excretion. Approximately 90% of the dose orally administered to rats and mice was excreted in the urine within 48 hours of dosing, with the majority (82%) being eliminated during the first 24 hours (Yakuri To Chiro 4: 510-514, 1976). Administration by oral gavage to rats resulted in 85%-93% of the administered dose being excreted in the urine within 7 days (Japanese Journal for Hygiene 35(4): 693-701, 1980). Elsisi et al report that 24% and 1% of the administered14C-DEP dose was excreted in the urine and faeces respectively after 24 hours following application to the dorsal skin of ratsFundamental and Applied Toxicology 12: 70-77 1989).

In humans, following daily whole body dermal application of DEP over one treatment week, the mean recovery rate of DEP in the urine was 5.8% as the mono-ester, MEP, with an unconjugated (free) fraction of up to 78%. The majority of MEP was excreted within the first 8 hours of application to the skin . The recovery rates recorded daily were between 0.3%-13.9%, indicating large intra-individual variations (International Journal of Andrology 31: 118-130, 2008).