Percutaneous absorption of [3H]tretinoin and systemic exposure to mequinol after dermal application of 2% mequinol/0.01% [3H]tretinoin (Solagé) solution in healthy volunteers.

Solagé is a combination product composed of 2% mequinol (4-hydroxyanisole) and 0.01% tretinoin (all-trans-retinoic acid) in an ethanolic solution, which is being studied for its safety and efficacy as a topical treatment for disorders of skin hyperpigmentation. The purpose of this study was to evaluate the extent of percutaneous absorption of [3H]tretinoin and to estimate the systemic exposure to mequinol from this combination product when topically applied to the backs of healthy subjects. Eight subjects received bid topical applications of nonradiolabelled 2% mequinol/0.01% tretinoin solution on a 400 cm2 area of the back for 14 days. The subjects then received a single topical application of 2% mequinol/0.01% [3H]tretinoin solution. After 12 h, the radiolabelled dose was removed and bid treatment with nonradiolabelled 2% mequinol/0.01% tretinoin solution was continued for 7 days. Plasma, urine and faecal samples were analysed for total radioactivity and plasma was analysed for both mequinol and tretinoin by GC/MS procedure. Mean percutaneous absorption of [3H]tretinoin based on the cumulative recoveries of radioactivity in the urine and faeces was about 4.5% (median 2.18%). Tretinoin concentrations in plasma did not increase above endogenous levels. This was consistent with the concentrations of radioactivity in plasma, which showed an average Cmax of 91 pg-eq/mL (median 26 ng/mL). Average Cmax and AUC(0-12 h) values for mequinol were 10 ng/mL and 33 ng h/mL, respectively. Based on the results of this study, systemic toxicity from topical application of tretinoin in this formulation is unlikely, because percutaneous absorption of tretinoin is minimal and because endogenous levels of tretinoin are not increased following bid dosing with this combination formulation. The safety of mequinol in this combination formulation is supported by the low systemic exposures of the subjects in this study compared with the systemic exposures at the highest doses in the dermal toxicity studies in mice (16.6-fold) and rats (34.6-fold).

Measurement of 2,4-toluenediamine in urine and serum samples from women with Même or Replicon breast implants.

The objective of this matched case-control study was to determine whether women with Même or Replicon polyurethane-covered silicone breast implants are exposed to clinically significant levels of free 2,4-TDA from biodegradation of the polyurethane foam. Urine and serum samples were obtained from 61 patients with Même or Replicon breast implants and 61 controls on two separate occasions separated by 10 +/- 3 days. Free TDA was analyzed by gas chromatography combined with negative chemical ionization mass spectrometry with lower limit of quantitation in both urine and serum of 10 pg/ml. The results were correlated with the length of time since implantation. No patients or controls had detectable free 2,4-TDA in their sera. Thirty patients had quantifiable levels of free 2,4-TDA, and 18 had detectable levels in their urine. Controls had no quantifiable levels, but 7 subjects had detectable levels. The biodegradative half-life of the polyurethane foam was estimated to be 2 years. A risk assessment using the cancer potency estimate calculated by the FDA from rat data and the National Academy of Sciences methodology provided a theoretical lifetime risk of approximately one in one million. It was concluded that the polyurethane foam cover on the Même and Replicon breast implants biodegrades. The risk assessment of approximately one in one million derived from this study strengthens earlier conclusions by the Health Protection Branch (Canada) that there is no significant risk of cancer from exposure to the 2,4-TDA formed from this biodegradation.