Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
A biomarker approach to measuring human dietary exposure to certain phthalate diesters
Author:
Anderson WAC, Castle L, Scotter MJ, Massey RC & Springall C
Year:
2001
Bibliographic source:
Food Additives and Contaminants, 18, 1068-1074

Materials and methods

Objective of study:
excretion
metabolism
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Human volunteers were administered a single oral dose of radiolabelled benzylbutylphthalate and the amounts of the monoester metabolites excreted in the urine were measured.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): benzylbutylphthalate
- Substance type: analytical reagent
- Physical state: no data
- Analytical purity: 99%
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling): no data
- Specific activity (if radiolabelling): no data
- Locations of the label (if radiolabelling): deuterium labelling on the aromatic ring
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: no data
- Storage condition of test material: no data
Radiolabelling:
yes

Test animals

Species:
human
Strain:
other: not applicable
Sex:
not specified
Details on test animals and environmental conditions:
HUMAN VOLUNTEERS
- no details provided

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: mixed with food
Details on exposure:
PREPARATION OF DOSE:
- spiked into margarine and administered on toast
- administered to volunteers as breakfast

HOMOGENEITY AND STABILITY OF TEST MATERIAL: no data
Duration and frequency of treatment / exposure:
single administration
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 253 and 506 µg/person (approx 3.6 or 7.2 µg/kg bw, based on a body weight of 70 kg)
No. of animals per sex per dose:
8 volunteers/group
Control animals:
yes
Positive control:
no
Details on study design:
- Dose selection rationale: did not exceed the daily exposure figures estimated from dietary surveys (MAFF, 1987, 1996)
- Rationale for volunteer assignment (if not random): no data
Details on dosing and sampling:
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: 24-hour urine samples collected during the day prior to dosing and during days 1, 2 and 6 days after dosing
- From how many volunteers: 8/dose; samples analysed individually, not pooled
- Method type(s) for identification of metabolites: HPLC-MS
- Limits of detection and quantification: no data
- Other:
- boric acid (~2 g/2-litre collection vessel) used as a preservative for the urine
- samples stored at -20 ºC between collection and analysis
- collection vessels made of polyethylene
- extraction method: enzymic hydrolysis of the glucuronide conjugates in urine, solvent extraction and clean-up, derivatization (no further details)
- method for assessment of chemical purity of metabolites: NMR and GC-MS
Statistics:
no

Results and discussion

Preliminary studies:
no

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Mean levels in urine for low- and high-dose groups respectively (7 volunteers/dose) +- relative standard deviation:
- Day 1 (24 hours after dosing)
- Monobenzylphthalate (MBeP): 140 µg (+- 39%), 323 µg (+-26%)
- Monobutylphthalate (MBuP): undetectable, 20 µg (+- 59%)
- Days 2 and 6 after dosing (24-hour collections):
- MBeP: undetectable
- MBuP: undetectable

Any other information on results incl. tables

Excretion yields for benzylbutylphthalate, on a molar basis, for the low- and high- dose groups respectively:

- Day 1 (24 hours after dosing):

- MBeP: 67% and 78%

- MBuP: undetectable, 6%

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
In a reliable human study, monobenzylphthalate was identified as the main metabolite and monobutylphthalate as a secondary metabolite after a single oral administration of benzylbutylphthalate 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.
Executive summary:

Groups of 8 human volunteers were administered 0, 253 or 506 µg benzylbutylphthalate in a radioactively-labelled, deuterated form (d4-BBP). The phthalate dose 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.

In the first 24-hours post dosing, the mean amounts of d4-monobenzylphthalate 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-monobutylphthalate (relative standard deviation 59%) was also excreted, representing a conversion rate of 6%, but at the low dose it was undetectable. Both metabolites were undetectable in urine collected during days 2 and 6 post-dosing.

In a reliable human study, monobenzylphthalate was identified as the main metabolite and monobutylphthalate as a secondary metabolite after a single oral administration of benzylbutylphthalate 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.