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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Administrative data

direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles.

Data source

Reference Type:
Repeated topical treatment, in contrast to single oral doses, with Vitamin A-containing preparations does not affect plasma concentrations of retinol, retinyl esters or retinoic acids in female subjects of child-bearing age.
Nohynek GJ et al.
Bibliographic source:
Toxicol Lett 163: 65-76

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
basic toxicokinetics
Test guideline
no guideline required
Principles of method if other than guideline:
Toxicokinetic study in humans; dermal and oral administration of retinol or retinyl palmitate.
GLP compliance:
not specified

Test material

Details on test material:
retinyl palmitate (CAS No. 79-81-2); according to the authors, purity was 100% (supplier: DSM Nutritional, Basel, Switzerland)


Type of population:
two groups of 14 female volunteers of child-bearing age
Ethical approval:
not specified
Route of exposure:
Reason of exposure:
Exposure assessment:
Details on exposure:
Dermal application: 3.5 +/- 0.5 g cream per day = approx. 16 +/- 2.7 mg per day= approx. 29700 +/- 5000 IU retinyl palmitate per day.
Formulations consisted of O/W emulsion cosmetic creams containing 0.55% all-trans retinyl palmitate (RP).
The concentration of the test substances in the respective formulations was verified by HPLC. For oral administration, RP, purity 100%, was received.
At the oral administration, study subjects received a suspension containing RP in pasteurised low-fat milk at 10000 IU or 30000 IU.

Twenty-eight healthy, non-pregnant women of child-bearing age participated in the study. Two groups of 14 volunteers were kept on a Vitamin A-poor diet and treated topically for 21 days with creams containing 0.55% retinyl palmitate on approximately 3000 cm² of their body surface area, amounting to a total of approximately 30000 IU Vitamin A/subject/day. After a 12-day wash-out period, the study groups received single oral doses of 10000 IU or 30000 IU retinyl palmitate (RP) , corresponding to the maximal EU allowance during pregnancy or three-times higher, respectively. Blood samples were collected over 24 h on study days minus 3 (pre-study), 1, 21 (first and last days of topical treatment) and 34 (oral administration) at 0, 1, 2, 4, 6, 8, 12, 14-16 h and 24 h after treatment for determination of plasma concentrations of retinol (REL), retinyl palmitate (RP), oleate (RO) and stearate (RS), 9-cis-, 13-cis-, all-trans- (AT), 13-cis-4-oxo or AT-4-oxo-retinoic acids (RAs).

Results and discussion

Results of examinations:
Plasma analysis results during topical treatment (study days 1 and 21): All individual or group mean plasma concentrations of REL, RP, RO, RS, or 13-cis-, 13-cis-4-oxo-, AT-, AT-4-oxo RAs remained within normal physiological limits and no statistically or biologically significant differences were seen when Day 1 or 21 mean AUC (0-24 h) and Cmax were compared to pre-study values.

Single oral doses of RP at 10000 IU or 30000 IU produced dose-related and sustained increases (up to 15 fold) in Cmax and AUC (0-24h) values of
plasma RP, RO, RS, 13-cis- and 13-cis-4-oxo-RAs, as well as a transient increase in AT-RA. However, no changes in mean or individual plasma concentrations (24 h AUCs and Cmax values) of REL, 9-cis-RA, AT- or AT-4-oxo-RAs were observed.

Any other information on results incl. tables

Single oral application of 10000 IU or 30000 IU retinyl palmitate, corresponding to the maximum allowed daily dose and of Vitamin A during pregnancy (and its 3 fold increased dose, respectively) produced

significant increases in plasma retinyl  esters and RAs. In contrast, no siginficant changes in REL, retinyl esters and RAs levels were observed after daily dermal application for 21 days of the same doses.

Applicant's summary and conclusion