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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Urinary metabolite excretion after oral dosage of bis(2-propylheptyl) phthalate (DPHP) to five male volunteers – Characterization of suitable biomarkers for human biomonitoring
Author:
Leng, G. et al.
Year:
2014
Bibliographic source:
Toxicology letters 231.2 (2014): 282-288.

Materials and methods

Objective of study:
excretion
Principles of method if other than guideline:
Oral dosing of 5 volunteers with 50mg labelled DPHP
Urine sampling for 48h
Selective determination of the three main DPHP urinary metabolites by HPLC-NESI-MS/MS
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(2-propylheptyl) phthalate
EC Number:
258-469-4
EC Name:
Bis(2-propylheptyl) phthalate
Cas Number:
53306-54-0
Molecular formula:
C28H46O4
IUPAC Name:
bis(2-propylheptyl) phthalate
Test material form:
liquid
Radiolabelling:
yes
Remarks:
ringdeuterated DPHP-d4

Test animals

Species:
human
Sex:
male
Details on test animals or test system and environmental conditions:
age: 27 - 49 years
body weight: 77- 94 kg
no occupational exposure to DPHP or other plasticizers

Administration / exposure

Route of administration:
other: oral
Vehicle:
other: dissolved in 0.25mL ethanol and mixed in edible waffle cup with a chocolate sufarce containing tea or coffee during breakfast
Duration and frequency of treatment / exposure:
single treatment
Doses / concentrations
Dose / conc.:
0.6 mg/kg bw/day
Remarks:
0.54 - 0.66 mg/kg/day
50mg per person
No. of animals per sex per dose / concentration:
5
Control animals:
other: pre-exposure values
Details on study design:
- Dose selection rationale: considerably below the lowest NOAEL for DPHP and comparable to the doses used in previous DINP and DINCH human metabolism studies, but several orders of magnitute above expected background exposure. Stable isotope labelled DPHP-d4 was used to fully exclude influences of background DPHP levels.
Details on dosing and sampling:
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: from 10:00 am pre-dosing for the next 48h. Times of sampling were recorded. 20 - 29samples per volunteer.
- Method type(s) for identification HPLC-NESI-MS/MS
- Limits of detection
0.1 mg/l for cx-MPHxP-d4
0.2 mg/l for OHMPHP-d4
0.2mg/l for oxo-MPHP-d4
- Limit of quantification
0.3 mg/l for cx-MPHxP-d4
0.5 mg/l for OHMPHP-d4
0.5mg/l for oxo-MPHP-d4
Statistics:
Exponential regression modeling
Metabolic half-time is given by the natural logarithm of two over k

Results and discussion

Main ADME results
Type:
metabolism
Results:
Main metabolites were oxo-MPHP (13.5%) and OH-MPHP (10.7%). Fractions as percentage of total oral dose excreted in urine within 48h.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
mono(propyl-6-oxo-heptyl) phthalate (oxo-MPHP)
mono(propyl-6-hydroxyheptyl) phthalate (OH-MPHP)
mono(propyl-6-carboxyhexyl)- phthalate (cx-MPHxP)

Any other information on results incl. tables

Predominant metabolites are OH-MPHP and oxo-MPHP. After 24h, 12.6% of the oral dose were excreted as oxo-MPHP, followed by OH-MPHP (9.9%), but only 0.42% as cx-MPHxP. The maximum in excretion was reached after 3.6 - 4h, depending on metabolite, but though excretion was rapid, all metabolites could still be detected after 48h. Summed up for all three measured metabolites 22.94% were excreted within 24h, which increased to 24.7% after 48h.

DPHP is metabolized to MPHP, which is in turn metabolized to OH-MPHP and to a much lesser extent to cx-MPHxP. OH-MPHP can be further metabolized to oxo-MPHP.

Applicant's summary and conclusion