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Description of key information

The available evidence suggests that Silatrizole has a low absorption via the oral and dermal route. Systemic absorption of this substance via inhalation route can be expected but to a limited extent. No information is available to assess metabolism or elimination. But the slow elimination and the high log Kow suggest that the substance can bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:
high bioaccumulation potential
Absorption rate - dermal (%):
1

Additional information

In accordance with the section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physical chemical characteristics of the substance, the results obtained from acute, repeated-dose, and reproductive toxicity studies, as well as information gained from genotoxicity assays were used to predict its toxicokinetic behaviour.


 


Physical-chemical properties:


The substance is a monoconstituant and whitish powder solid at room temperature having a relatively high molecular weight (approx. 500 Da). The particle size distribution of the substance was determined to be 17.5% < 10 µm and 1.5% > 500 µm. The MMD was determined to be lower than 27 µm. The substance has a very low water solubility (0.04 mg/mL at 20°C) and is highly lipophilic based on the octanol/water partition coefficient (log Kow > 6 at 22°C). The substance has low volatility according to its vapour pressure (2.10E-13 Pa à 25°C).


 


Absorption:


Oral/GI absorption


- In an acute oral gavage toxicity study, no mortality was observed in male and female rats at the limit test dose of 2000 mg/kg bw (oral LD50 > 2000 mg/kg bw).


- The 13-week repeated dose toxicity gave a NOAEL of 1000 mg/kg bw/day, i.e. the highest dose-level tested in this study. Changes observed in clinical biochemistry parameters(lower glucose level in females, higher cholesterol level in males, higher creatine kinase activity in males, higher sodium level in females and changes in some plasma protein fractions of the protein electrophoretic pattern) were not considered to be adverse. However the minor variations in clinical biochemistry parameters could suggest that some absorption of Silatrizole and/or metabolites from the gastrointestinal tract took place, with distribution via the bloodstream to the organs.


 


- The 26-week repeated dose toxicity also gave a NOAEL of 1000 mg/kg bw/day, i.e. the highest dose-level tested in this study. Slightly lower glucose levels were noted but were not considered to be adverse.


 


- In the study of fertility and early embryonic development, the NOAEL for fertility and early embryonic development was 1000 mg/kg bw/day, i.e. the highest dose-level tested in this study. A slightly lower body weight gain and food consumption during the premating period in females of the top dose-group was noted.


- In the study of the effects on pre- and post-natal development,the NOAEL for fertility and early embryonic development was also 1000 mg/kg bw/day, i.e. the highest dose-level tested in this study. Slight reduction in body weight gain and food consumption were noted during the gestation and/or lactation periods of treated females but were considered to be of no toxicological importance. Body weight was reduced in pups from all treated groups, from day 14 post-partum. This slight effect was considered to be possibly related to the reduced food consumption of the (P) dams.


 


- In the developmental toxicity study, the NOAEL for adult toxicity and developmental toxicity was 1000 mg /kg bw/day. Slightly reduced food consumption during the dosing period in the dams at the top-dose was considered to be incidental.


 


The results from toxicological tests do not allow to conclude on the level of oral or cutaneous absorption of the substance. It is indeed not possible to know if the absence of effects directly attributable to the substance is due to its very low toxicity or to its very low systemic absorption.


The very low hydrosolubility of the substance suggests that the absorption will be low but the high lipophilicity (log Kow > 6) suggest that the substance can be retained in the body.


 


The oral absorption of Silatrizole was demonstrated in groups of rats including in a GLP-compliant subchronic repeated dose oral toxicity study conducted according to the OECD Guideline 408 (1981), Silatrizole was administered by gavage to a satellite group of Sprague Dawley rats (5/sex/dose) at daily doses of 0 and 1000 mg/kg bw for 13 weeks in order to obtain plasma samples at 4 and 13 weeks of treatment. In plasma levels of the rats treated with 1000 mg/kg bw/day, a total mean value of 1.096 ± 0.427 µg test article/ml plasma was measured. The mean value for male rats was 0.968 ± 0.545 µg/ml (1.112 ± 0.682 µg/ml dosed at week 4 and 0.824 ± 0.333 µg/ml dosed at week 13) and for female rats 1.224 ± 0.216 µg/ml (1.158 ± 0.205 µg/ml dosed at week 4 and 1.290 ± 0.168 µg/ml dosed at week 13). There exists no statistical difference between plasma levels of male and female rats.


 


In the 26 weeks repeated oral toxicity study, rats were administered 0, 100, 300 and 1000 mg/kg/day of the substance by gavage. The systemic exposure to the test substance was observed in all animals at all test treated dose levels in weeks 4, 13 and 26, at both 30 minutes and 24 hours after treatment. The mean plasma levels were generally slightly higher 24 hours after dosing than 30 minutes after treatment at all dose-levels, indicating a slow and sustained absorption (or reabsorption) of the test substance. In addition, at all time-points, the levels were moderately to markedly higher in females than in males, except in week 4 at 100 mg/kg bw/day where the plasma levels were considered to be similar, suggesting a gender difference in the pharmacokinetic of the test substance. Both the C30min and C24hrs values increased linearly but not proportionally with the dose-level.


 


The oral absorption of Silatrizole was also demonstrated in groups of rats included in another study where two groups of 9 males Sprague-Dawley rats were administered a single oral dose of 1000 mg/kg bw of the radiolabeled (14C) test substance Silatrizole, prepared in 2 different vehicles (0.5% aqueous solution of methylcellulose and Tween 80, or corn oil) in order to compare the absorption extent of the test substance. The comparison of pharmacokinetics parameters showed that the absorption was more rapid in 0.5% aqueous solution of methylcellulose and Tween 80 than in corn oil. Plasma levels in terms of Cmax were similar in both groups (2.08 vs 1.63 µg-eq/g for CMC+Tween 80 and corn oil,respectively). These results indicate that the substance is systemically absorbed after oral administration.


 


Dermal absorption


Regarding dermal absorption, systemic absorption by the dermal route is expected to be low based on the physchem properties. This is supported by the absence of mortality observed in the acute dermal toxicity study (LD50 > 2000 mg/kg bw).


The low dermal absorption of Silatrizole was also demonstrated in a study where one group of 10 male and 10 female hairless rats received the radiolabeled (14C) test substance Silatrizole, once by cutaneous application in a formulation which contained the test substance at 15% or 75 mg/kg. The majority of resorption (Tmax) was achieved within 1 h for males and 8 h for females and the percentage of administered dose which was present in plasma was inferior to 1%.


The very low hydrosolubility of the substance suggests that the absorption will be low but the high lipophilicity (log Kow > 6) suggest that the substance can be retained in the body.


 


Respiratory absorption


The potential for inhalation toxicity was not evaluated in vivo.


The vapour pressure of the substance (Vp = 2.10E-13 Pa at 25°C) indicated a very low volatility and inhalability.However, the test substance is a powder andthe particle size distribution of the substance was determined to be 17.5% < 10 µm and 1.5% > 500 µm. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. Therefore an exposure by inhalation can be anticipated. However, considering the particle size and the very low hydrosolubility of the substance suggests that the absorption will be low but the high lipophilicity (log Kow > 6) suggest that the substance can be retained in the body.


 


Distribution:


Any material that is absorbed will be distributed via the blood to the liver, and other organs and tissues. The moderate water solubility of the substance would limit distribution in the body via the water channels. Due to the expected slow elimination, the substance as such could accumulate in the body fat.


 


Metabolism:


Three in vitro studies assessed the potential genotoxicity of Silatrizole both with and without auxiliary metabolic activation. An Ames test (Wollny, 1996) gave negative results with no indication of cytotoxicity either with or without metabolic activation. A chromosome aberration test (Czich, 1996) showed no structural aberration and limited cytotoxicity in the presence or absence of metabolic activation. A HPRT test (Wollny, 1996) showed no structural aberration and no cytotoxicity in the presence or absence of metabolic activation. As such, these studies confirmed that Silatrizole does not have genotoxic potential but did not provide any information on metabolism. The absence of significant systemic effects in animals exposed to doses up to 1000 mg/kg bw/day cannot permit to conclude on metabolism.


 


No studies to identify metabolites have been carried out.


 


Excretion:


In the study where one group of 10 male and 10 female hairless rats received the radiolabeled (14C) test substance Silatrizole, once by cutaneous application in a formulation which contained the test substance at 15% or 75 mg/kg. The majority of resorption (Tmax) was achieved within 1 h for males and 8 h for females and the percentage of administered dose which was present in plasma was inferior to 1%. The total radioactivity measured in the plasma decreased slightly and was still higher than the limit of quantitation at the last time of sampling (72 h after application) indicating a slow elimination of the test substance or its metabolites.


 


In the 13/26 weeks repeated oral toxicity study, the plasma levels seen in weeks 13 and 26 were generally greater than those of week 4 (time effect) for females given 300 mg/kg/day and for all animals given 1000 mg/kg/day. The results suggest a dose- and sex-dependent accumulation of the test substance, reaching approximately 3 µg/ml in females of the 1000 mg/kg/day group in week 26.


 


A substance that was not absorbed from the oral route is mainly excreted in the faeces.


 


No metabolic pathway or other route of elimination can be deduced based on the available data.


 


Accumulative potential:


Based on the available data demonstrating a low absorption of the substance by oral or dermal route but a slow excretion, and taking into consideration the high log Kow and the very low water solubility values, the substance is expected to bioaccumulate.