4,4'-isopropylidenediphenol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2015

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Research Conducted by the National Toxicology Program (Research Triangle Park, NC) with Participation from FDA (Jefferson, AR)

Data source

Reference

Reference Type:

publication

Title:

Pharmacokinetics of bisphenol A in humans following a single oral administration.

Author:

Thayer, K. A., Doerge, D. R., Hunt, D., Schurman, S. H., Twaddle, N. C., Churchwell, M. I., Garantziotis, S., Kissling, G. E., Easterling, M. R., Bucher, J. R., and Birnbaum, L. S.

Year:

2015

Bibliographic source:

Environment International. 83:107-115.

Materials and methods

Objective of study:

absorption

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Six men and eight women were exposed to 100 μg/kg bw of deuterated Bisphenol A (d6-BPA) by oral administration and blood and urine analysis were conducted over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) Bisphenol A. The following parameters are reported: rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates."

GLP compliance:

not specified

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

not specified

Details on test material:

A single dosing solution (10 mg/mL) was prepared by dissolving d6-BPA in absolute ethanol (USP grade, Decon Laboratories, King of Prussia, PA). Aliquots of 0.5 and 1 mL were placed in sealed screw-top glass vials, and stored chilled until just before dosing. The initial concentration of d6-BPA in the dosing solution (10 μg/μL) was verified by LC/MS/MS and concentrations in stored aliquots were always within 10 % of the initial amount (range 93–106 %).

Radiolabelling:

other: deuterated BPA (d6-BPA)

Test animals

Species:

human

Strain:

other: Men and non-pregnant women were recruited in 2012–2013 from the Raleigh Durham region of North Carolina, USA.

Sex:

male/female

Administration / exposure

Route of administration:

other: Subjects were fed a vanilla wafer cookie containing a dose of 100 μg/kg bw of d6-Bisphenol A after fasting starting at 12 midnight on the day of the visit.

Vehicle:

other: A single dosing solution (10 mg/ml) was prepared by dissolving d6-Bisphenol A in absolute ethanol. Aliquots of 0.5 and 1 ml were placed in sealed screw-top glass vials, and stored chilled until just before dosing.

Duration and frequency of treatment / exposure:

Single treatment

Doses / concentrations

Remarks:

Doses / Concentrations:
100 µg/kg

No. of animals per sex per dose:

six men and eight women

Control animals:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

other: Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711 nM (390 ng/ml) was observed at Tmax of 1.1 ± 0.50 h.

Results:

Unconjugated d6-BPA appeared in serum within 5–20 min of dosing with a mean Cmax of 6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 ± 0.52 h.

Main ADME results 2

Type:

other: The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPAwere 6.4±2.0 h and 6.2±2.6 h, respectively.

Results:

Recovery of total administered d6-BPA in urine was 84–109%. Most subjects (10 of 14) excreted >90% as metabolites within 24 h.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Main metabolite: Bisphenol A-glucuronide in addition Bisphenol A-sulfate was identified and bis-conjugates.

Any other information on results incl. tables

Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711 nM (390 ng/ml) was observed at

Tmax of 1.1 ± 0.50 h. Unconjugated d6-BPA appeared in serum within 5–20 min of dosing with a mean Cmax of

6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 ± 0.52 h. Detectable blood levels of unconjugated or total d6-BPA

were observed at 48 h in some subjects at concentrations near the LOD (0.001–0.002 ng/ml). The half-times

for terminal elimination of total d6-BPA and unconjugated d6-BPAwere 6.4±2.0 h and 6.2±2.6 h, respectively.

Recovery of total administered d6-BPA in urine was 84–109%. Most subjects (10 of 14) excreted >90% as metabolites

within 24 h.

Applicant's summary and conclusion

Executive summary:

"Conclusions: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated Bisphenol A comprising less than 1% of the total d6-Bisphenol A in blood at all times. Elimination of conjugates into urine largely occurs within 24 h."

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