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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetics (Oral route):

In the key study for toxicokinetics, i.e. an oral toxicokinetic study acc. to OECD 417 and GLP,groups of 4 male and 4 female rats were each given a single oral dose of 50 mg [14C] Bemotrizinol /kg bw to investigate the systemic exposure, tissue distribution and metabolite profiles (CTL UR0698, 2002). The excretion of radioactivity in urine and faeces was monitored for 4 days after dosing. After this period, the rats were killed and residual radioactivity was measured in blood, selected tissues and the remaining carcasses. An additional group of 9 male and 9 female rats were each given a single oral dose of 50 mg [14C]- Bemotrizinol /kg bw and radioactivity was measured in blood and plasma over a 24 hour time course after dosing.

Excretion was rapid and extensive in both male and female rats. Urinary excretion accounted for mean totals of 0.1% and 0.2% of the dose and faecal excretion accounted for mean totals of 94% and 97% of the dose for males and females respectively. The only component in the faecal extracts was identified as the parent compound Bemotrizinol. Therefore, unchanged Bemotrizinol represented all of the dose excreted in faeces. Residues in the tissues were very low and accounted for <0.01% of the dose in total in both males and females. The mean radioactivity remaining in the residual carcass accounted for 0.3% of the dose for males and 0.1% for females. The total recoveries of administered radioactivity were approximately 95% for males and 97% for females. The concentration of radioactivity in blood and plasma was below the limit of detection at all time points up to 24 hours after dosing.

In conclusion, following a single oral dose of 50 mg [14C]-Bemotrizinol /kg bw to male and female rats, the excretion was rapid in both sexes, with 94-97% of the administered dose excreted directly in faeces within 96 hours as unchanged Bemotrizinol. This is consistent with the measured concentrations of radioactivity in blood and plasma of less than the limit of detection over a 24 hour time course after dosing. Quantitatively, no sex difference was observed. Urinary excretion accounted for 0.1-0.2% of the dose, and residual radioactivity in tissues and carcass accounted for 0.1-0.3% of the dose. Residues in individual tissues were all <0.01 % of the dose. Under the chosen testing conditions, it is considered, that the absorption of Bemotrizinol after oral administration is very low.

 

Dermal absorption:

In the key study for dermal absorption, [14C]-Bemotrizinol was dermally applied in a 4% formulation at two different dose volumes in male Wistar rats (CTL UR0722, 2002). The applications were designed to simulate potential human dermal exposure to the formulation during normal use. A measured amount (54 µl or 22 µl) of each formulated dose was applied on shaved skin (10 cm2) per rat under semiocclusive conditions for 6 hours, corresponding to doses of 2 mg and 0.8 mg Bemotrizinol per animal. After a 6 hour exposure, groups were either terminated or the application sites of the remaining rats were washed to remove the unabsorbed dose. Urine, faeces and cage wash were collected from each cage after the 6 hour skin wash, and then at daily intervals after dosing for the duration of each experiment. Groups of four rats were terminated at 6, 24, 72 and 120 hours after dosing. The skin was washed to remove unabsorbed residual dose, before exsanguination. The application site skin was tape-stripped to remove the stratum comeum. All samples, including selected tissues and residual carcasses were analysed for radioactivity.

Following dermal exposure to the high dose (2 mg [14C]-CGF-C1607), the majority of the applied radioactivity (86-93%) was washed from the skin surface using soap solution and water. Much lower fractions remained associated with the application site (i.e. 1.2%-1.6% in the stratum corneum and 0.2%-0.7% in the remaining skin) and some of this was available for absorption. The residue associated with the application site declined slightly at later time-points. The concentrations of radioactivity in blood and plasma were below the limit of detection at all time points investigated. The content found in tissues or excreted in urine was 0.01% of the applied dose or less. In faeces, less than 0.05% was found up to 24 hours after dosing, however at later time points small residues were noted due oral uptake by chewing site definition devices. The mean amount of dose absorbed (in urine, faeces, cage wash, tissues, G.I. tract with contents, residual carcass) remained approximately constant during the different timepoints (0.15-0.21% of the applied dose) when excluding animals showing oral ingestion of the test substance or incomplete skin wash.

Following dermal exposure to the low dose (0.8 mg [14C]-CGF-C1607), similar results were obtained. The majority of the substance was washed from the skin surface (94% - 98%) and lower fractions remained associated with the stratum corneum (0.9%-1.6%) and the remaining skin (0.3%-0.5%) of the application site. These residues associated with the application site also declined slightly at later time-points. Urine and tissue content was less than 0.01% and up to 0.03% was found in faeces up to 72 hours, whereas small residues were noted in faeces at the 120 hour timepoint due to incidental oral uptake. Concentrations in blood and plasma were below the limit of detection and the mean amount of dose absorbed (in urine, faeces, cage wash, tissues, G.I. tract with contents, residual carcass) remained approximately constant (0.12-0.31% of the applied dose) when excluding animals showing oral ingestion or leakage of the test substance.

The authors considered the radioactivity present in the skin beneath each application site as unabsorbed, although it was recognized, that some of this material may be absorbed beyond the duration of exposure investigated. While the fraction found in the stratum corneum would not be regarded as bioavailable, the content in the remaining skin was added as potentially bioavailable to the absorbed doses as a worst case approach. Accordingly, the mean percentages in the remaining application site skin was added to the means of the absorbed doses per timepoint and the bioavailable fraction of [14C]-CGF-C1607 in the high dose is 0.8%, 0.7%, 0.5% and 0.4% of the applied dose 6, 24, 72 and 120 hours, respectively. For the low dose groups, the bioavailable fraction is 0.6%, 0.8%, 0.5% and 0.8% of the applied dose 6, 24, 72 and 120 hours, respectively.

In conclusion, following a 6 hour exposure period to 2 mg or 0.8 mg [14C]-CGF-C1607 applied as a 4% formulation, the absorption of the test substance was very low

 

In line, in a 90 day repeated dose dermal study, measurements of plasma concentrations of the test item showed very low percutaneous absorption (CIT 25378, 2004, see chapter 7.5.3).

 

Low demal absorption was confirmed in in vitro studies with human skin samples, consisting of the stratum corneum and the viable epidermis. However, the dermis was not included in the present study. The skin penetration of Bemotrizinol (10% in a representative sunscreen formulation) was assessed over a 24 hour period after application to human skin at a target dose of 2 mg/cm2 (An-eX CSC/1d/97, 1998). A modified receptor phase (6% Oleth 20 in phosphate buffered saline, pH 7.4) was used and the solubility of Bemotrizinol in this medium was 16 µg/ml. Of the 12 skin samples treated with Bemotrizinol, 4 showed some permeation and 1 of these was excluded on the basis of anomolously early and high permeation. The average data from the remaining 11 cells showed a relatively long lag phase of over 8 hours followed by very slow permeation of Bemotrizinol through the skin (with a maximum flux of 1 ng/cm2/hr). Overall permeation through the skin was very low (i.e. 15 ± 8 ng/cm2 representing 0.006 ± 0.003 % of the applied dose after 24 hours).

In a comparable study under same testing conditions, the content of Bemotrizinol was additionally assessed in tape strips and the remaining skin (An-eX CSC/8/98, 1998). Of the 12 treated skin samples, 6 showed permeation of Bemotrizinol through the skin and into the receptor phase, although 1 of these was excluded from further analysis on the basis of anomolously early and high permeation. The permeation through the skin was very low, i.e. 40±20 ng/cm2, representing 0.02±0.01 % of the applied dose after 24 hours. The determination of Bemotrizinol levels on and in the skin after 24 hours revealed, that the majority of the recovered test substance (>80 % of the applied dose) was found either on the skin surface or in the first 3 tape strips. Remaining Bemotrizinol was recovered in tape strips 4-20 (10.2 % of the applied dose), the remaining skin (7.3 %) or the receptor phase (<0.1 %).

 

In conclusion, Bemotrizinol has a very low potential for absorption via the dermal route.

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