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Description of key information

Short description of key information on bioaccumulation potential result: 
Two toxicokinetics studies were done with Uvinul A Plus:
In one bioavailability study a low to medium bioavialabilty of Uvinul A plus was measured. The calculated bioavailability was about 26% and 45% in male and female animals respectively after single oral administration of 14C-Uvinul A Plus to rats at a dose level of 100 mg/kg bw.
One plasmakinetic study was conducted with crystalline and molten Uvinul A plus administered in a single low and high dose. At the low dose for both applications, a peak level of Uvinul A Plus and its free acid metabolite in plasma was reached within 1 hour after application. No Uvinul A Plus and less than 10% of the maximum plasma peak level of its metabolite were detected 24 hours after dosing. At the high dose, elimination was slower- Uvinul A Plus and its acid metabolite reached plasma peak levels within 8 hours. 24 hours after dosing plasma concentrations of Uvinul A Plus were less than 10 % of the peak values whereas the Uvinul acid metabolite was still approx 20% of the peak value for rats dosed with crystalline Uvinul A Plus. The study has also shown that there is no significant difference in the resulted systemic dose between the two forms of Uvinul A Plus.
Short description of key information on absorption rate:
The absorption rates of Uvinul A Plus in in vivo and in vitro studies using different species ranged from 0.042 – 10.34 %. In a rat in vivo study a mean absorption of 3 % of the applied radiolabelled Uvinul A Plus was measured. The estimated in vivo human absorption rate via the skin of Uvinul A Plus is calculated as 0.15 %, based on the results of the vivo study conducted in rats, and the interspecies comparison based on the in vitro study with human skin (0.54 %) and the in vitro study using rat skin (10.34%).

Key value for chemical safety assessment

Absorption rate - dermal (%):
0.15

Additional information

Toxicokinetic Assessment of Uvinul A Plus

 

General

Uvinul A Plus is produced at an EU manufacturing site (Germany). Uvinul A Plus is an oil soluble UVA filter that can be readily incorporated in the oil phase of emulsions. The substance is used as an ingredient in cosmetic products, mainly in sunscreen products as UV absorber alone or in combination with other UV absorbers.

Uvinul A Plus is a pasty melt at room temperature with a molecular weight of 397.514 g/mol. The partition coefficient (logPow = 6.2) was determined by HPLC. The substance’s water solubility was determined to be 16 µg/l at 20°C.

 

Absorption

Low dermal uptake was expected due to the low water solubility of the substance. The rate of penetration may also be limited because of the high log Pow of 6.2. Nevertheless, uptake into the stratum corneum is expected be high.

This estimation based on physical-chemical parameters is in line with four different skin absorption (penetration) studies performed with Uvinul A Plus. The absorption rates of Uvinul A Plus in all the four in vivo and in vitro studies using different species ranged from 0.042 – 10.34 %. In a rat in vivo study a mean absorption of 3 % of the applied radiolabelled Uvinul A Plus was measured. In the three in vitro studies conducted with human, rat and porcine skin specimens a mean absorption of 0.54 %, 10.34 % and 0.042 % of the dose applied was measured, respectively.

The estimated in vivo human absorption via the skin of Uvinul A Plus is 0.15 %, based on the results of the in vitro study with human skin, the in vitro and in vivo studies conducted with rat skin. The in vivo human skin absorption was calculated with the in vivo skin absorption result in rats, and the absorbance of Uvinul A Plus in the rat and human in vitro studies:

Conversion factor = % absorbance rat in vitro study / % absorbance human in vitro study

% absorbance in vivo human= % absorbance in vivo rat study / conversion factor

This figure is confirmed by the Scientific Committee on Cosmetic Products and Non-Food Products (2006) giving a maximum percutaneous absorption rate of 0.31 µg/cm2 equivalent to 0.149 %.

In a study on the method development for a human biomonitoring method of Uvinul A Plus in urine (HBM study), 5 volunteers were dermally treated with a sunscreen containing 10% Uvinul A Plus (59 mg/kg bw). Based on the three main urinary metabolites (AHB, EHB and DHB), the estimated dermal resorption rates were 0.0034 - 0.0214 % of the applied dose (Scherer 2019).

Upon dermal contact, the toxicity of Uvinul A Plus is expected to be very low due to a low bioavailability, as no acute toxicity after oral administration occurred up to 2000 mg/kg bw. Furthermore, application of Uvinul A Plus to skin of rabbits did not cause any irritation or corrosion. Applied to the skin of guinea pigs, no sensitising effects were observed.

The compounds relatively high Log Pow value and the low water solubility indicate that Uvinul A Plus may be taken up in the body by micellular solubilisation, e.g. after oral administration.

In a bioavailability study 14C-Uvinul A Plus in olive oil was administered to 24 female and male, bile catheterized Wistar rats in a single oral dose by gavage at dose level of 100 mg/kg bw. The mean total recovery of radioactivity was found to be 79.84 % and 88.05% of the applied in male and female rats, respectively. Total excretion of radioactivity via bile within 72 hours was 11.28 % of the administered dose for male rats and 19.76 % of the administered dose for female rats. Total excretion of radioactivity via urine after 72 hours was 13.79 % of the administered dose for male rats and 22.62 % for female rats. Mean radioactivity remaining in the carcass after sacrifice was 0.46% and 1.26 % of dose for male and female rats. In the cage wash, 0.71% (male animals) and 1.46 % (female animals) of dose were recovered. Based on the added values of the percentage of dose values of urine, cage wash, carcass and bile, the bioavailability of Uvinul A Plus in Wistar rats at a dose level of 100 mg/kg bw was about 26 % and 45 % for male and female animals, respectively.

One plasmakinetic study in rats was conducted with crystalline and molten Uvinul A Plus administered orally in a single low and high dose. At the low dose for both application forms, a peak level of Uvinul A Plus and the related free acid metabolite in plasma was reached within 1 hour after application. No Uvinul A Plus and only less than 10 % of the maximum plasma peak level of its metabolite were detected 24 hours after dosing. At the high dose, elimination was slower- Uvinul A Plus and the related acid metabolite reached plasma peak levels within 8 hours. 24 hours after dosing plasma concentrations of Uvinul A Plus were less than 10 % of the peak values whereas the acid metabolite was still 48% of the peak value for rats dosed with crystalline Uvinul A Plus. Based on the results shown a short half life for Uvinul A Plus in the body is expected.

 

Distribution and Metabolism

Toxicity to orally administered Uvinul A Plus is very low, as shown in acute to subchronic toxicity tests. High dose effects in kidneys (2-generation study) indicate systemic distribution after oral application. Uvinul A Plus and a related free acid metabolite are present in the rat blood plasma (see plasmakinetic study above). Uvinul A plus is thus believed to be distributed in the body and rapidly excreted via the faeces and urine (see below). The relatively low BCF-value of 166.8 indicates that Uvinul A Plus is not likely to be bioaccumulative. This assumption is also confirmed by the 14C bioavailability study (see above) as only 0.46% and 1.26 % of dose for male and female rats remained in the carcass of the sacrificed rats after 72 h.

When bioavailable, after e.g. ingestion or penetration of skin, Uvinul A Plus is found to be metabolized. The formation of a free acid metabolite could be shown in rats (see plasmakinetic study above). Metabolism may transform Uvinul A Plus into more polar degradation products. Likely pathways are reactions such as hydroxylation. Parent compound and metabolites formed in phase I metabolic reactions may be rendered more polar by phase II metabolism in subsequent steps. Possible metabolites such as hydroxyl derivatives may undergo conjugation before excretion in the bile.

In humans (i.e. the HBM study), urine of Uvinul A Plus treated volunteers contained ethylamino-hydroxybenzoyl-benzoic acid (EHB; 33% of the applied dose), amino-hydroxybenzoyl-benzoic acid (AHB;16% of the applied dose) and diethylamino-hydroxybenzoyl-benzoic acid (DHB; 5% of the applied dose) as main metabolites (Scherer 2019). Most of DHB (90%), 63% of EHB and 31% of AHB was identified as glucuronides. Furthermore, single hydroxylated species of the 3 main metabolites were detected in the urine of the volunteers but estimated to be present at 100 fold lower concentration than the main metabolites EHB, AHB and DHB. The parent compound Uvinul A Plus was not found in the urine.

It is unlikely that Uvinul A Plus is metabolised to more reactive (toxic) products. This assumption is supported by results obtained in oral toxicity studies and different in vitro tests. In acute and subchronic in vivo studies toxicity was rather low. In Ames tests, chromosome aberration assays and a mouse lymphoma test no significant increase in toxicity was noted in the presence of a rodent microsomal S9-fraction, when compared to incubation without S9-fraction. Together, this data indicates that formation of reactive metabolites is rather unlikely.

 

Excretion

Based on molecular weight and water solubility, the substance is expected to be most likely excreted via the faeces. Meabolites are also likely to be excreted via the urine. A bioavailability study with 14C-Uvinul A Plus (see above) showed that the absorbed substance is excreted via bile (11.28 % male, 19.76 % female) and urine (13.79 % male, 22.62 % female) after 72 hours. The substance was nearly completely excreted within 72 hours, as only 0.46 and 1.26 % of dose for male and female rats remained in the carcass after sacrifice.

In humans (i.e. the HBM study), 54% of a single oral dose of Uvinul A Plus (0.295 mg/kg bw in Ethanol/water) was excreted in urine after 72 hours, based on AHB, EHB and DHB as the three main urinary metabolites (Scherer 2019).

 

Conclusion

Uvinul A Plus revealed a low skin penetration rate in humans (estimated fraction of 0.15 % of the applied dose). Thus, bioavailability after skin contact is very limited. If administered orally the substance is well absorbed (present in plasma after 1-8 h, 26 – 45 % of total dose absorbed), distributed in the body and excreted via the faeces and urine. The expected short half live time in blood plasma as well as the low BCF of 166.8 indicate that Uvinul A Plus does not bioaccumulate.

 

Discussion on bioaccumulation potential result:

Bioavailability study:

In a bioavailability study (key study, BASFAG02B0496/046024) 14C-Uvinul A Plus in olive oil was administered to 24 female and male, bile catheterized Wistar rats in a single oral dose by gavage at dose level of 100 mg/kg bw.

The mean total recovery of radioactivity was found to be 79.84 % and 88.05% of the applied dose in male and female rats, respectively. Total excretion of radioactivity via bile within 72 hours was 11.28 % of the administered dose for male rats and 19.76 % of the administered dose for female rats. Total excretion of radioactivity via urine after 72 hours was 13.79 % of the administered dose for male rats and 22.62 % for female rats. Mean radioactivity remaining in the carcass after sacrifice was 0.46 % and 1.26 % of dose for male and female rats. In the cage wash, 0.71 % (male animals) and 1.46 % (female animals) of dose were recovered.

Based on the added values of the percentage of dose values of urine, cage wash, carcass and bile, the bioavailability of Uvinul A Plus in Wistar rats at a dose level of 100 mg/kg bw was about 26 % and 45 % for male and female animals, respectively.

This study is classified acceptable and satisfies the guideline OECD 417 requirements.

 

Plasmakinetic study:

One plasmakinetics study in rats (key study, BASFAG02B0408/996060) was conducted with Uvinul A Plus. 16 male Wistar rats in four groups were administered via feed with either crystalline or molten Uvinul A Plus in nominal dose levels of 1000 ppm (corresponded to 25.2 and 23.4 mg/kg bw of crystalline and molten Uvinul A Plus respectively) and 10,000 ppm via feed (corresponded to 245.4 and 127.1 mg/kg bw of crystalline and molten Uvinul A Plus respectively). Blood samples were taken before dosing and 1, 2, 4, 8, and 24 hours after feed dosing and plasma concentrations of Uvinul A Plus and the respective free acid of Uvinul A Plus were determined.

At the low dose of 1000 ppm plasma concentrations of Uvinul A Plus and its free acid metabolite reached mean peak levels (Cmax) of about 120 ng/ml Uvinul A Plus and 1274 ng/ml of the acid for crystalline Uvinul A Plus and mean peak values of 335 ng/ml and 1542 ng/ml of Uvinul A Plus and the acid respectively for the molten substance, already within 1 hour after application (Tmax= 1 hour).

After having reached peak levels, plasma concentrations declined with indications for an enterohepatic circulation. At 24 hours after dosing, no Uvinul A Plus was detectable in the plasma samples and plasma concentrations of the respective acid were less than 10 % of the maximum plasma peak levels.

At the high dose of 10000 ppm elimination of the test substance was - as expected - slower (probably due to saturation of the elimination/ distribution mechanisms): plasma concentrations of Uvinul A Plus and the related free acid metabolite reached mean peak levels (Cmax) of about 7116 ng/mL Uvinul A Plus and 9237 ng/mL of the acid for the crystalline Uvinul A Plus and mean peak values of 3278 ng/mL and 6645 ng/mL of Uvinul A Plus and the acid respectively for the molten substance, within 8 hour after application (Tmax= 8 hours). At 24 hours after dosing, plasma concentrations of Uvinul A Plus were less than 10 % of the maximum values whereas plasma concentrations of the acid were still 1604 and 391 ng/mL for the crystalline and molten Uvinul A Plus, respectively. Results of the molten form at this high dose should be taken with cautious due to palatability problems with feed containing molten Uvinul A Plus.

In both doses, a comparison of the calculated AUD demonstrated no significant difference of the systemic dose between the crystalline and the molten Uvinul A Plus and altogether no significant differences were detected in the rate and extent of absorption of the crystalline and the molten Uvinul A Plus after dosing via feed.

Discussion on absorption rate:

In an in vivo study in male Wistar rats (BASFAG01B0496/046023) an absorption of radioactivity following a single dermal administration of 14C-Uvinul A Plus in a formulation with 10% unlabeled Uvinul A Plus was measured. Three groups of four animals were exposed for 12 hours to radio-labelled Uvinul A plus in a nominal dose level of 0.81 mg/cm2 (corresponding nominally to about 8.1 mg/animal and about 2.6 mg/kg body weight). The recoveries of radioactivity were examined immediately after exposure and 24 and 120 hours after exposure in the second and the third group respectively. The amount of radioactivity absorbed (excreta, cage wash, carcass, blood cells and plasma) was about 2.96% of the dose applied after the 12 h exposure period. At sacrifice, after 24 and 120 h, the absorptions were 2.31% and 3.16% respectively. Virtually no radioactivity remaining in the skin after the end of exposure penetrated through the skin during the 5-days post observation period.

 

Permeability and permeation of Uvinul A plus were examined by four in vitro studies: A study (BASFAG52H0496/049111) conducted with skin specimens from human donors and a study conducted with skin specimens from rat (BASF-50H0496/049112) were chosen as key studies for interspecies comparison. Furthermore a study was conducted with porcine skin (BASFAG51H0636/029032). In the three studies, experiments were conducted according to the OECD 428 guideline and SCCP requirements with skin dermatomized to approximately 500 µm in a Franz (static) cell system followed by skin tape stripping (after skin wash) and skin extraction both done for measuring the concentration of Uvinul A Plus in the stratum corneum and in deeper skin layers. All skin specimens from the different species were exposed for 24 hours in the Franz cell system to a mean dose of 1803.3 µg (human skin specimens), 1804 µg (rat skin specimens), and 200 µg/cm2 (porcine skin specimens) of pure Uvinul A Plus. In parallel to experiments with Uvinul A Plus, permeability of caffeine was carried out in skin samples of the same donors in all three studies to ensure the quality of the skin samples.

In the three studies, the highest mean recovery rate was found in the samples from the skin wash procedure (ranged from 77 - 99%). Absorption was calculated from the measurement values obtained from the receptor fluids and deeper skin (second pool of tape stripping and skin extraction after tape stripping). The absorption through human skin was calculated to be 0.54% of the applied dose of Uvinul A Plus. The highest absorption was determined through rat skin resulting in 10.34% of the dose applied. The absorption in porcine skin was 0.042% of the dose applied. Slow penetration of Uvinul A plus in vitro trough porcine skin was confirmed in an older study (BASFAG51H0408/992300) using porcine epidermis samples according to the draft OECD 428 guideline (Dec. 2000).

The estimated in vivo human absorption via the skin of Uvinul A Plus is 0.15 %, based on the results of the in vitro study with human skin, the in vitro and in vivo studies conducted with rat skin. The in vivo human skin absorption was calculated with the in vivo skin absorption result in rats, and the absorbance of Uvinul A Plus in the rat and human in vitro studies:

Conversion factor = % absorbance rat in vitro study / % absorbance human in vitro study

% absorbance in vivo human= % absorbance in vivo rat study / conversion factor

This figure is confirmed by the Scientific Committee on Cosmetic Products and Non-Food Products (2006) giving a maximum percutaneous absorption rate of 0.31 µg/cm2 equivalent to 0.149 %.

Based on the main urinary metabolites in human volunteers of the HBM study, the dermal resorption rates of Uvinul A Plus were estimated in an even lower range of 0.0034 - 0.0214 % of the applied dose (Scherer 2019).