Lab Notes

Arbutin converts to Hydroquinone in the skin???

In previous SCCS opinions (SCCS/1552/15 and SCCS/1550/15), the EU SCCS had concerns that the effects of AB on the skin are mainly due to the gradual hydrolysis and release of Hydroquinone (HQ). They also expressed concern about the aggregate exposure to HQ if Arbutin were supplied with residual HQ. This is why they called for data from July 2020 to April 2021 to establish Arbutin's stability, dermal absorption, HQ release rate and aggregate exposure. In general, HQ is theoretically produced from a-AB through the following methods:

1) Raw material contamination
2) Arbutin degradation (either in formulations or by glucosidases)
3) Microbial conversion

Hydroquinone contamination

DSM, one of the biggest raw material manufacturers, provided new data on the quantitation of HQ in Alpha Arbutin using HPLC and determined that the HQ content was lower than the Limit of Quantitation (LOQ) of 3 ppm. The SCCS was satisfied with the improved method and accepted the results.

Alpha-Arbutin Stability

In previously shown data from SCCS/1552/15, the stability of 2-3% solutions of alpha-Arbutin was assessed at pH of 4.5, 5.0 and 6.0 using HPLC. The aqueous samples were stored at 50C for 28 days and measured weekly for purity and HQ content. The results showed that alpha-Arbutin was stable, and HQ was not detected.

Another experiment tested the stability at pH 3.5, 4.5, 5.5, and 6.5 at 40C for 3 months by HPLC. It was concluded that the stability of alpha-Arbutin is pH dependent, with the highest stability at a pH of 5.0. No HQ was detected during the experiment.

Newly submitted data tested the stability of alpha-Arbutin in Polyethylene bags inside Aluminum bags as supplied commercially. After 36 months in 40C, alpha-Arbutin remained stable with HQ content below LOQ (3 ppm).

The photostability of alpha-Arbutin was also assessed through exposure to normal daylight, 8 hours per day over 12 months, and no hydroquinone was detected in the samples suggesting no photo-catalyzed degradation occurred.

Various formulations containing alpha-Arbutin were also examined, and after accelerated stability testing, alpha-Arbutin (even up to 7%) remained stable, and no HQ was detected.

Enzymatic and Microbial Conversion

Experiment 1

They used pig skin and human skin in Franz diffusion cells and applied 1% or 2% of alpha-Arbutin cream. The receptor fluid and the skin samples were processed and analyzed by HPLC, and the recovery rate for both are around 91% and 93%, respectively. Hydroquinone measurements did not reveal quantifiable amounts. SCCS commented that this experiment is of limited value given the study design.

Experiment 2

Pig skin and human skin homogenates were incubated with alpha-Arbutin solutions (pH 5.4, 6.4, and 7.4). They concluded that alpha-Arbutin hydrolysis is pH dependent, increasing from 5.4 to 7.4. This enzymatic degradation yields hydroquinone which is rapidly oxidized to benzoquinone. SCCS noted that since there is only one human subject, they can't conclude anything regarding the degradation rate. In addition, the experiment included antibiotics, so the degradation seen is purely from glycosidases in the skin.

Experiment 3

This in-vitro study used pig and human skin washed after arbutin application. The resulting chromatograms revealed 93.4% for Arbutin, with 3% Hydroquinone and 3.5% unknown of the total radioactivity recovered. SCCS commented that antibiotics seemed to reduce the degradation, but no further conclusions can be made since data is missing on human skin.

Experiment 4

Fifteen subjects were asked to apply a cream containing either 2% alpha-Arbutin or a placebo for four days. Tape strips were taken for baseline and after four days. The strips were then processed and analyzed using HPLC, and the results showed the recovery rate for alpha-Arbutin is 42 +/-23%, while only 0.073+/-0.065% of AB degrades to HQ. The SCCS commented that there is no mass balance of the applied a-AB, and the amount applied in the four consecutive days was not considered for the recovery of a-AB. They also noted that stripping was only done on day four, so it is hard to know the fate of the previously applied a-AB. The final comment is that this study is not accepted as the methodology was insufficiently described.

Experiment 5

The previous experiment was improved, and they increased the subject number to 17 and increased the tape-stripped samples to 14 layers to account for deeper layers. Pipettes for dosing and gloves for product distribution were also analyzed to be included in mass balance calculation. After 1 hour of application, the HPLC-UV quantitation revealed a recovery rate of 93.7% for alpha-Arbutin and HQ levels were below the Limit of Detection. The SCCS agreed with the conclusion that alpha-Arbutin is stable both on the skin surface and on deeper layers.

Final SCCS opinion

The panel calculated the maximum exposure rate by applying a worst-case scenario and declared that alpha-Arbutin is safe, up to 2% in facial products and 0.5% in body products.


We agree that ample evidence supports the stability and non-conversion of AB to HQ. However, it would've been more significant if they'd tape-stripped the skin hourly for 6 hours. We know firsthand that tape-stripping studies are a pain in the butt as they are tedious and literally painful. It is borderline unethical to ask volunteers to sit tight without moving their arms for 6 hours. Still, it would've been more enlightening to see those results.