Octocrilene

Endpoint summary

Additional information

No key study for the toxicokinetics of octocrilene is available. Based on its physicochemical properties, such as poor water solubility (40 µg/L at 20°C) and high logPow (6.1), octocrilene is a lipophilic compound, which is likely to be absorbed in the GI tract by micellular solubilization. Oral repeated dose and reproductive/developmental toxicity studies showed evident systemic effects, that can be based on systemically available octocrilene, which further confirms its oral absorption capabilities. Due to the very low vapour pressure (4*10^-7 Pa at 20°C), the inhalative uptake of octocrilene as a vapour is low.

Concerning metabolism, the present oral repeated dose and reproductive/developmental toxicity studies as well as a mechanistic study identified the capacity of octocrilene to induce xenobiotic enzyme induction (BASF 2019; 99C0495/00S048). Therefore, a significant metabolism of octocrilene in the liver can be expected when being absorbed from the gastrointestinal tract. Based on the chemical structure of octocrilene, the metabolism may consist of:

·        Hydrolysis of the ester binding by esterases and formation of 2-cyano-3,3-diphenyl-2-propenoic acid and 2-ethylhexanol.

·        Oxidation of both hydrolysis products by cytochrome P450-dependent monooxygenases.

·        Cytochrome P450-dependent decarboxylation of 2-cyano-3,3-diphenyl-2-propenoic acid.

·        Glucurono-/ Sulfo- or GSH-conjugations of metabolic oxidation products.

In an in vitro study on the hydrolysis-stability in rat liver S9 fraction, gastric-juice simulant and intestinal-fluid simulant containing porcine pancreas lipase, octocrilene was found to be metabolized in liver S9 fraction only (BASF 2013; 09B0743/11B009). One metabolite (not further specified) was detected that was more polar than the parent compound octocrilene. The mean metabolic turnover values in liver extracts after a 2 hour incubation were 40 or 70% dependent on the octocrilene concentrations used, whereas no detectable metabolization and no metabolite was found in the intestinal-fluid simulant. Lower peak areas of octocrilene were found after incubation in gastric juice simulant as compared to respective controls, which implies a partial hydrolyzation. However, the polar metabolite observed in incubates of liver S9 fraction, wich can be attributed to the degradation product, was not detected in the gastric juice test system. Overall, these data demonstrated, that octocrilene was degradable in liver S9 fraction but was found to be stable in intestinal-fluid simulant.

 

Concerning excretion, an extensive metabolization, leading to polar metabolites with low molecular weights, followed by renal excretion is to be expected based on the data available. A dark yellow discoloration of the urine specimen has been observed in the subchronic repeated dose toxicity study after test substance application (BASF 1993; 50S0227/92059), supporting, that renal excretion may be a relevant pathway for elimination of octocrilene metabolites containing chromophore structures.

 

Dermal absorption

No key study for the dermal absorption of octocrilene is available. This endpoint has been assessed in a weight of evidence based on all available in vitro and in vivo data.

In the present dermal 90-day study, the only toxicologically relevant finding was local irritation at the site of test substance application. Lack of histopathological or clinical hematology abnormalities indicate, that the dermally applied octocrilene has only a low bioavailability.  

A cosmetic formulation containing 8% octocrilene was applied at 3 mg formulation/cm2 for a 16-hour period on freshly dermatomed human skin (344 ± 61 µm) in static diffusion cells in vitro (Potard 1999b). Stratum corneum (from 16 tape strippings); epidermis, dermis, receptor fluid and washing solution was assessed by HPLC. Low amounts (0.1% and 0.005%) of the applied dose was found in epidermis and dermis respectively, whereas 4.3% of the applied dose was found in the stratum corneum. No octocrilene was detectable in the receptor medium. Thus, the amount bioavailable, i.e. the amount of octorilene in epidermis, dermis and receptor medium, represents approx. 0.1% of the applied dose.

A cream formulation with 8% octocrilene was applied for 16 hours (3 mg formulation/cm2) on freshly dermatomed pig (700 ± 50 µm) and human (350 ± 50 µm) skin in static diffusion cells in vitro (Beiersdorf 1998). Stratum corneum (from 16 tape strippings); epidermis, dermis, receptor fluid and washing solution was assessed by HPLC. In the pig and human skin sample setup, no octocrilene was detectable in the receptor medium. In pig epidermis and dermis, 2.8% and 0.3% of the applied dose were found and 14% were detected in the stratum corneum. In human epidermis and dermis, only 0.125% of the applied dose were found, whereas 5.4% was determined for human stratum corneum. Based on these data the amount bioavailable (epidermis, dermis and receptor medium) represents approx. 0.2% of the applied dose in the human skin setup and approx. 3% of the applied dose in the pig skin setup.

Additional studies, applying 8% octocrilene in a cream formulation on human skin samples in vitro and in vivo for 30 min showed a good correlation in the absorption into the stratum corneum between the different experimental setups and the in vitro data confirmed the low bioavailability when dermally applied to human skin (Potard 1999a). However, no values were provided for epidermis, dermis, and receptor medium. In an additional publication of the same authors, the dermal application of 8% octocrilene in a cream formulation on human skin samples in vitro for 30 min showed values below the detection limit in 88%, 90% and 100% of individual values for epidermis, dermis and the receptor fluid samples (Potard 2000). After 16 h exposure under the same conditions, 90% and 100% of individual values were below the detection limit for dermis and receptor fluid samples. An average of 90% of octocrilene found in the stratum corneum was present in the first 6 tapes and an average of 94% in the first 8 tape strips. Since no values were provided for epidermis, dermis, and receptor medium, a bioavailable fraction of octocrilene cannot be deduced by the presented set of data.

In a publication by Jungmann et al., octocrilene (1 µmol/cm2) was applied in ethyl acetate to full thickness human skin for 22 hours (Jungmann 2012). Three pooled tape strips, epidermis, dermis and liquid receptor samples were quantified by HPLC. No octocrilene was detectable in the receptor medium but considering the total amount applied, 19%, 14% and 3% of the applied dose was found in human stratum corneum, epidermis and dermis respectively. However, some results were inconsistent in reporting and a clear differentiation between stratum corneum and epidermis is not ensured due to insufficient tape stripping. Further, no info on skin sample integrity and overall recovery is provided by the authors, which question the validity of the results.

In a study available as short summary from a secondary source, 10% octocrilene in a formulation was applied for a 16-hour period on human skin in vitro (TSCAT 1993). The amount of octocrilene in the dermis and receptor medium was 0.04% of the applied dose each, whereas 0.54% was determined in the stratum corneum. No values were provided specifically for epidermis samples. Therefore, assessment of a bioavailable fraction of octocrilene is not fully possible. However, a cutanous absorption at or below 0.1% of the applied dose is indicated by these results.

Overall, the dermal absorption rate of octocrilene was found to be low, and a maximum of 0.2% is considered for further assessment in a weight of evidence.