Registration Dossier

Toxicological information

Exposure related observations in humans: other data

Administrative data

exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Clinical evaluation of pharmacokinetic absorption using human subjects

Data source

Referenceopen allclose all

Reference Type:
Percutaneous absorption (PA) of phenols in vivo
Bucks, D.A.W. et al
Bibliographic source:
Clin. Res., 35 (3) 672 A (1987)
Reference Type:
Percutaneous penetration and mass balance accountability: technique and implications for dermatology
Bucks, D.A.W., et al.
Bibliographic source:
J Toxicol - Cut & Ocular Toxicol 9 (2) 439-451 (1989/1990)

Materials and methods

Type of study / information:
Dermal absorption of 4-aminophenol in human volunteers
Endpoint addressed:
dermal absorption
Test guideline
no guideline available
Principles of method if other than guideline:
Application of known quantity of radioactively labelled compound under controlled conditions and collection of urine for quantification
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:


Ethical approval:
confirmed, but no further information available
Details on study design:
The percutaneous absorption of PAP was evaluated in a study using 5 human volunteers.
2 μg/cm² of 14C-labelled PAP in 95% ethanol was applied to the bend of the forearm over a total
surface area of 2.5 cm². The application time was not specified. Urine from each subject was
collected over a seven day period and the radioactivity recovered was quantified.
Exposure assessment:
Details on exposure:
The 14C -labeled 4-aminophenol (Miravek Biochemicals, Inc., Brea, CA) was applied in 95% ethanol solution to the ventral forearm of healthy male volunteers (n≥5).
Chemical and radioactive dosages were 2-4 μg/cm² and 1 μgCi cm², respectively.
The area of application was 2.5 cm² and the dose was administered in 20 μL of volatile solvent.
In site-covered studies after evaporation of the vehicle (0.5 min.), the application site was either covered with an occlusive, semirigid, polyethylene-vinyl acetate copolymer, chamber or a nonocclusive, “ventilated,” modified chamber. In both cases, the chambers were affixed to the skin with hypoallergenic adhesive tape. The nonwoven, absorbent cotton pads with which the chambers are supplied were removed prior to use.
The subjects collected their urine for 7 days after application of 14C-labelled 4-aminophenol. Urine volumes were determined gravimetrically for each time period, and duplicate 3-5 mL aliquots were analyzed for radioactivity. The percentage of “dose” ( as total radioactivity) excreted was determined for each time interval. At 24 hr after dosing, the chamber was removed, placed in scintillation fluid, and the sequestered 14C quantified (since the chamber is in direct contact with skin). The application site was washed using a standardized procedure with five cotton balls consecutively soaked in soap solution (Ivory Liquid Soap, Procter and Gamble Co., Cincinnati, OH, diluted 1:1 with water), water, soap solution, water, and water. All washes were collected and processed for liquid scintillation counting to assay for residual surface 14C-labelled 4-aminophenol. For the remaining 6 days of the urine collection period, the administration site was again covered with a new chamber. Finally, this chamber was also assayed for 14C-labelled chemical by liquid scintillation counting. The application site was also washed as described above. In the latter studies, after being washed, the stratum corneum at the site of application was striped 10 tomes with adhesive tape and the skin tape strips analyzed for residual radioactivity by liquid scintillation counting.

Results and discussion

The dermal absorption of PAP was determined to be 13% (study published in 1987) of the applied dose. In a subsequent study
performed by the same investigators using similar dosing and urine collection regimens,
penetration was determined to be 6-8% (study published in 1989).

Any other information on results incl. tables

Table 1. Accountability of applied 14C in percentage of dose (1989/1990 publication)

Percutaneous Absorption 1st
Occluded study 8.1 15 36 1.8 2.4 63
Protected study 6 30 48 2.6 3 1.6 91

Applicant's summary and conclusion

Two studies in humans evaluating absorption of 4-aminophenol were conducted and it was determined that absorption under occluded conditions when ethanol was used as a solvent was between 6 and 13%. For the purposes of risk assessment, it can be assumed that about 10% absorption of a potential dermal exposure may be absorbed based on the available data and therefore a factor of 10 may be used as the difference between oral and dermal absorption.