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Description of key information

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2014), an assessment of the toxicokinetic behaviour of the target substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical properties and studies in which the toxicokinetic behaviour of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione was investigated.

Based on ADME studies it was observed that 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione is nearly completely absorbed after oral exposure. As worst case also a 100% absorption rate is assumed for dermal and inhalation route. Furthermore, it was shown that the test substance is distributed in the whole body but also eliminated fast so that no bioaccumulation potential is given. The metabolic pathway of the test substance is shown in the attachment. The test substance was shown to be excreted rapidly; within approximately 48 hours, measured as the total cumulative excretion of urine, faeces and expired air. Male rats excreted the test substance mainly via faeces whereas female rats showed excretion to almost equal parts in urine and faeces.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100

Additional information

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2014), an assessment of the toxicokinetic behaviour of the target substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical properties and studies in which the toxicokinetic behaviour of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione was investigated.

2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione is a mono-constituent substance with a molecular weight of 442.91 g/mol. The substance is a solid at 20 °C with a melting point of app. 115 °C at 1013 hPa, water solubility of 64.2 g/L at 20 °C and vapour pressure of 1.8E-10 Pa at 20 °C. The log Pow was estimated to be -1.9 at pH 7 and 1 at pH 4.0 (measured as 1.9 at pH 2) and the pH was 3.37 at 20.9°C (1% pure substance in distilled water).

Absorption

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts; this mechanism is important for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (ECHA, 2014).

In an in vivo ADME study performed according to OECD guideline 417, a single dose of 2 and 200 mg/kg bw radiolabelled Phenyl-UL-¹⁴C 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione was administered via gavage to 4 Wistar rats/sex (ADME, 2005). The absorption rate was 94.35% for low-dose males and 94.35% for low-dose females, respectively; while the absorption rate for high-dose males was 97.46% and for high-dose females 87.37%, respectively. The absorption rate was measured as the recovery rate from urine, bile and organs/tissue. The Tmax was 0.13 – 0.31 h in the low-dose animals, and 0.8-1.0 h in the high-dose animals. In other studies performed to assess specific parts of the ADME process, the recovery rate was similarly 91 – 104% of the administered dose; measured as recovery in organs/tissues and excreta, or in excreta alone (residue depletion and metabolism, 2006; ADME bile excretion, 2006; distribution and excretion, 2006). The results of the studies show that the substance is rapidly and almost completely absorbed from the GI-tract.

In several oral repeated dose toxicity studies, treatment-related systemic effects were observed following administration of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione (IUCLID Section 7.5.1; 90-days rat, 2003; 90-days, mouse, 2003; 24-month, rat, 2006). Taking into account the available information, the oral absorption rate is considered to be 100%.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2014).

The log Pow is predicted to be > - 1.9 < 1 at the pH of the skin (4.5 - 5.5). The log Pow and molecular weight of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione indicate that the substance is likely to be absorbed at a low to moderate rate via the skin.  QSAR estimation resulted in a dermal absorption of 0.01876 µg/(cm2*h) considering a log Pow of -1.9 and 1.539 µg/(cm²*h) with a log Pow of 1.

In a 28-day repeated dose dermal toxicity study, the NOAEL was considered to be 10 mg/kg bw/day, based on the treatment-related microscopic findings observed in the pancreas, in animals administered 100 and 1000 mg/kg bw/day (key, 2013). The observed adverse effects show that the substance is absorbed through the skin, although it is not possible to quantify the rate of absorption. In conclusion, the dermal absorption rate of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione is considered to be 100%.

Inhalation

2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione is a solid with very low vapour pressure (1.8E-10 Pa at 20 °C), and therefore low volatility. Under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be negligible (ECHA, 2014). However, the substance may be available for inhalatory absorption after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). 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. Particles deposited in the nasopharyngeal/thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and swallowed. The particle size distribution of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione shows that the average of the median particle size D50 was 26.7 µm while the D10 was 7.7 µm. 90% of the particle volume or particle mass had a lower particle diameter than 100.2 µm (D90). This indicates that a significant fraction of the substance has the potential to be inhaled and will primarily be deposited in the nasopharyngeal/thoracic region. A minor fraction (> 10 < 50%) may penetrate into the alveolar region following exposure via the inhalation route.

No treatment-related systemic effects were observed in the acute inhalation toxicity study (key, 2004). However, as for the oral route treatment-related systemic effects were observed in oral repeated dose toxicity studies, while no treatment-related effects were observed in the acute toxicity study, it is not possible to make a reliable prediction for the inhalation route based on the acute toxicity study. Due to the limited information available a worst-case approach is taken and absorption via inhalation is assumed to be as high as via the oral route.

Distribution and Accumulation

The 4 available studies assessed different aspects of the distribution and potential for accumulation of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione in the rat.

In the ADME study (2005), the distribution of the test substance from the central compartment (plasma) to the organs and tissues was followed by measuring the concentration of the total radioactivity in plasma (0-48 h after administration). The maximum plasma concentration (Cmax) value was significantly higher for low-dose males (3.4 μg/g) than for low-dose females (1.9 μg/g). This was followed by a fast initial elimination phase (t1/2e(1)) of 1.1 h (low-dose males) and 0.3 h (low-dose females), a slower intermediate elimination phase (t1/2e(2)) of 2.4 h (low-dose males) and 3.0 h (low-dose females) and a moderate terminal elimination phase (t1/2e(3)) of 17.8 h (low-dose males) and 27.3 h (low-dose females). The area under the curves (AUC(0-∞)) indicated a slightly higher systemic exposure for low-dose males (4.0 μg/g x h) than for low-dose females (2.7 μg/g x h). In low-dose males, significantly lower values were calculated for the elimination rate constant (k1e = 4.7 h) and the mean residence time (MRT = 2.0 h) compared with the corresponding values in low-dose females (k1e = 48.5 h; MRT = 9.1 h).

Similar Cmax values were noted for high-dose males (277 μg/g) and high-dose females (284 μg/g). Compared with the low dose tests, these plasma concentrations were nearly proportional to the dose ratio. This indicated that the absorption process was not (over)saturated at the high-dose level. This was followed by a fast initial elimination phase (t1/2e(1)) of 0.1 h (high-dose males) and 0.5 h (high-dose females), a slower intermediate elimination phase (t1/2e(2)) of 2.0 h (high-dose males) and 1.4 h (high-dose females) and a moderate terminal elimination phase (t1/2e(3)) of 16.0 h (high-dose males) and 12.3 h (high-dose females). The area under the curves (AUC(0-∞)) indicated a slightly higher systemic exposure for high-dose males (1250 μg/g x h) than for high-dose females (933 μg/g x h). In high-dose males, a higher value was calculated for the elimination rate constant (k1e = 30.5 h) and a slightly lower for the mean residence time (MRT = 4.0 h), compared with the corresponding values in high-dose females (k1e = 12.8 h; MRT = 4.2 h).

The comparison of the absorption phases of the kinetic curves between the low- and high-dose groups showed a broader maximum for the high-dose animals. The maximum concentration (Cmax) was reached later at the high-dose level than at the low-dose level, and the following initial elimination phase was definitely longer in the high-dose than in the low-dose level. The curves at the end of the terminal elimination phase were comparable between the sexes. The AUC-values for males and females of the low dose and high dose groups indicated that the parent compound and/or its metabolites showed a disproportionately higher systemic exposure at the high dose level (i.e. >300-fold), which was probably due to an apparent saturation of the initial elimination/ biotransformation processes.

In addition to plasma concentration at different time points, the radiolabelled residues in the organs and tissues of the animals were determined at sacrifice, 72 h after the oral administration. Negligible amounts of radioactivity was found in the skin (0.01 - 0.02%) and gastrointestinal tract (0.01 - 0.04%). No significant sex-related differences were observed for the residues in the organs and tissues. In the low-dose animals, 5.6 and 6.3% of the administered dose was detected in the organs of male and female rats, respectively. In the high-dose animals, low percentages (0.1%) were found in the organs of both sexes. The highest equivalent concentrations were detected in the liver (2.1 - 5.4 ppm) and kidney (0.6 - 1.9 ppm), which are the organs responsible for the degradation and excretion of the test substance. These values were not correlated with the administered dose between the low- and high-dose groups. It is likely that tissue binding sites were more or less saturated with test item-related radioactivity already at the low-dose level. The concentrations in the other organs and tissues (except gastrointestinal tract) were low (0.0005 - 0.0067 ppm in the low-dose groups and 0.04 - 0.65 ppm in the high-dose groups).

In the second ADME study (ADME bile excretion, 2006), performed according to OECD guideline 417, a single dose of 2 mg/kg bw radiolabelled Phenyl-UL-¹⁴C 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione was administered via gavage to 8 Wistar rats/sex. The percentage of labelled substance/metabolites was measured 48 h after administration. The recovery of radioactivity in the organs and carcass (= sum organs/tissues minus the gastrointestinal tract) at sacrifice was 5.74% for the males and 7.14% for the females. For the gastrointestinal tract, the recovery was 0.63% for the males and 1.09% for the females. The respective values for the skin were below 0.1% for males and females. In the blood (measured in erythrocytes and plasma), the recovery percentage was < 0.01% in males and < 0.03% in females. These results are similar to those reported in ‘ADME, 2005’. In addition, by cannulating the rats, the recovery in bile could be measured: 52.5% of the administered dose was detected in the bile of the males and 22.4% of the dose of the administered dose was detected in the bile of the females 4 h after dosing.

In the third in vivo study performed according to OECD guideline 417, a single dose of 3 mg/kg bw radiolabelled Phenyl-UL-¹⁴C 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione was administered via gavage to 8 Wistar rats/sex (residue depletion and metabolism, 2006). In a control group 1 rat/sex was administered a single dose of 3 mg/kg bw 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione and treated according to the same protocol. The total radioactive residues (TRR, expressed as percentage of administered dose) was measured in the organs and tissues at sacrifice (0.5, 24 and 168 h). In (male and female) rats sacrificed 0.5 h post-dosing, 22.5 - 24.1% of the dose was detected in the organs and tissues, 55.4 - 65.5% in the gastrointestinal tract plus faeces and 2.8 – 11.4% in urine. During the first 24 h, the percentage of the dose in the organs declined to 3.3 - 3.7% and increased to 9.6 – 38.7% in the urine and 56.7 - 87% in the gastrointestinal tract plus faeces fraction. These values did not change significantly within the whole testing period of 7 days (168 h); indicating fast distribution of the absorbed compound related radioactivity within the body. The highest TRR-values in the organs of the rats were detected in the liver and kidney, which are the primary sites for metabolism and excretion. From day 1 to day 7, the values in liver and kidney decreased by 3 - 13% and 26 - 29%, respectively, to levels of 2.42 – 2.83% and 0.11 – 0.16%. Within the same period the values for erythrocytes and other blood corpuscles, plasma, skin and the carcass decreased to ≤ 0.05%.

In the fourth in vivo study performed according to OECD guideline 417, a single dose of 3 mg/kg bw radiolabelled Phenyl-UL-¹⁴C 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione was administered via gavage to 8 Wistar rats/sex (distribution and excretion, 2006). In a control group 1 rat/sex was administered a single dose of 3 mg/kg bw 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione and treated according to the same protocol. One animal/sex/time point was sacrificed 1, 4, 8, 24, 48, 72, 120 and 168 h after administration. The qualitative distribution of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione in organs and tissues was measured by quantitative whole body autoradiography (QWBA), while the radioluminography (RLG) technique was used to quantify the amount of radiolabelled substance in tissues and organs. This method allows the visualisation of selective enrichments of radioactivity.

In measuring the qualitative distribution, the more intense the blackening of the radioluminograms, the higher is the concentration of the radioactivity in the organs or tissues. One hour after oral administration, the radioactivity was distributed among almost all organs and tissues. The most intense blackening was found in the stomach, the small intestine, the urinary bladder, the liver, and the kidney. Less blackening was found in the blood, heart, and lung (males) and blood, brown (subcutaneous) fat, adrenal gland, uterus, ovary, thyroid, heart, and lung (females), respectively, followed by the other organs and tissues with decreasing intensity of blackening. Little blackening was found in the nasal mucosa, brain, spinal cord, and vitreal body of the eye. These results demonstrate that the test substance was readily absorbed. 4 hours after dosing the radioactivity in all peripheral tissues has decreased considerably with only weak blackening to be seen. Significant blackening could still be detected in the blood, heart, lung, spleen and testes (males), and blood, heart, lung, spleen, adrenal gland, thyroid and ovary (females), respectively. The highest concentrations of radioactivity were present in the excretory organs kidney, liver and in the gastro-intestinal tract for males and females. 8 hours after oral administration, the result was similar to the previous one. The most intense blackening was found in the contents of the large and small intestine as well as in the liver and kidney. 24 hours after administration, the extent and intensity of blackening in most organs and tissues had further decreased in the animals. High blackening was still observed in the contents of the large intestine, the kidney and the liver. Weak blackening could be seen in blood, adrenal gland, heart, and lung of females. In the radioluminograms of the rats sacrificed 48 hours, 72 hours, 120 hours, and 168 hours after oral administration, no blackening above the background could be observed for the organs and tissues, except kidney, liver, and the gastro-intestinal tract. These results demonstrate the fast depletion of test substance-related radioactivity from all peripheral compartments of the rat.

Among the quantitatively analysed organs, tissues, and fluids, the highest equivalent concentrations were observed in the liver, kidney and blood. Moderate peak concentrations were found in the lung and myocardium, brown fat, skin, salivary gland, thyroid, adrenal gland and the reproduction organs. Lower concentrations were reached in all other organs and tissues. The lowest peak concentrations were found in the spinal cord, the brain, and the eye. From peak values, a continuous decrease of radioactivity concentrations by several orders of magnitude, below the limit of quantification was observed for most organs and tissues within 48 hours in male rats and within 24 hours in female rats. High concentrations of radioactivity persisted in kidney and liver of both male and female rats for the whole test period of 7 days indicating significant retention and very slow elimination from these organs.  

The available studies consistently show that the level of parent compound and metabolites is reduced rapidly in most organs (to below the limit of detection within 48 h). In the liver and kidneys the elimination rate is slower, though continuous. 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione and its metabolites will not accumulate in organs or tissues.

Metabolism

In the 2006 ADME study (ADME bile excretion, 2006), the metabolism of 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione was quantified and the major metabolites were identified. In males > 80% of the parent compound was metabolised, in females > 60% was metabolised. The HPLC-profiles of urine, bile and faeces samples were very similar for males and females. No typical conjugates (for example with glucuronic acid or sulphate) were detected in the bile samples. The identification rate was high and parent compound and metabolites constituted in total 85.35% of the administered dose in males (test 1) and 86.71% in females (test 2). In males, unknown metabolites accounted in total for 0.57% of the dose in the urine, 3.94% in the bile and 0.39% in the faeces extract, respectively. In females, unknown metabolites accounted in total for 1.04% of the dose in the urine, 2.10% in the bile and 0.57% in the faeces extract. No individual unknown metabolite had a higher concentration than 0.7% of the dose in the urine, 0.8% in the bile and 0.3%% in the faeces.  

The parent compound was present only at low levels in male rats, with 6.30% detected in bile and excreta. The opposite was the case for female rats, where the results showed significantly higher values (14.08% in the urine and 24.82% in total). Significant sex differences were also seen for the quantity of metabolites detected in the respective samples. The extent of metabolism was greater in males than in females, while higher values were generally found in the bile samples for both males and females. The tetrahydrofurane ring of the molecule was the preferred site for metabolism. No metabolic changes were detected at the phenyl ring and cyclohexyl ring. Parent compound-hydroxy-pentanoic acid was the major metabolite. The values of all other metabolites were significantly lower. From this group, 5-oxo-THF, oxo-pentanoic acid and dihydroxy-pentyl were identified.

The identification of metabolites was elucidated further in a residue depletion and metabolism study performed in rats administered 5 mg/kg bw radioactively labelled 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione via gavage (residue depletion and metabolism, 2006). Plasma samples were drawn 0.5, 24 and 168 h post-administration, along with urine and faeces. The amount of parent compound and major metabolites was quantified in the (plasma, urine and faeces) samples and in liver, kidneys, carcass, skin and GI-tract at the same time intervals. The identification rate of the metabolites was more than 92% of the total radioactive residue (TRR) for the plasma, liver and kidney samples. The amount of parent compound and metabolites in plasma samples of both sexes was very low (< 1.5% of the administered dose) and decreased during the test period to around the limit of detection after 24 h and below after in the 168 h samples. This indicated a relatively rapid depletion of all radioactive components from the plasma. The major component was the parent compound and prominent metabolites were parent compound-hydroxy-pentanoic acid and -5-oxo THF. Only traces of parent compound -oxo-pentanoic acid were detected in the plasma of male rats. The amount of the total radioactive residues in the extracts from liver and kidney of both sexes was in the same order of magnitude. The parent compound was by far the most significant component in these samples especially in female rats. As for urine and plasma samples, the prominent metabolites were parent compound -hydroxypentanoic acid and -5-oxo THF. All other metabolites such as parent compound -hydroxybenzylic alcohol, -benzylic alcohol, -dihydroxy-pentyl and -oxo-pentanoic acid were detected in lower amounts. The metabolism of parent compound in rat follows oxidative processes and was more pronounced in male rats. Reactions took place primarily at the tetrahydrofuran ring of the molecule. The first metabolic reaction was an oxidative and obviously important step at the tetrahydrofuran ring of the molecule by which 5-oxo-THF metabolite was formed. Hydrolytic cleavage of the lactone ring led to the major metabolite parent compound -hydroxypentanoic acid. Further changes at the ring-opened structure occurred on a quantitatively lower level. All other reactions including cleavage of the tetrahydrofuran ring were of minor importance. The estimated parent compound -oxo-pentyl-urea metabolite was a trace metabolite detected in the urine of female rats by the LC-MS analysis. This compound was not seen in the HPLC-chromatograms that were used for quantification due to an obviously lower sensitivity of this method. It was therefore excluded from quantification. Based on this information, the conclusion is that the metabolism of the parent compound follows oxidative processes and is more pronounced in male rats. Reactions took place at the tetrahydrofuran ring of the molecule by which 5-oxo- THF metabolite was formed. Hydrolytic cleavage of the lactone ring led to the major metabolite parent compound -hydroxy-pentanoic acid. Further changes at the ring-opened structure occurred on a quantitatively lower level. All other reactions including cleavage of the tetrahydrofuran ring were shown to be of minor importance. Similar results of the identity and concentration of parent compound and major metabolites isolated from urine and faeces were reported in the 2005 ADME study.

The metabolic pathway proposed for the parent compound (from: residue depletion and metabolism, 2006) is found in the attachments of this section.

      

Excretion

The test substance was shown to be excreted rapidly; within approximately 48 hours, measured as the total cumulative excretion of urine, faeces and expired air (distribution and excretion, 2006). Significant sex differences were observed. In male rats primarily faecal excretion was observed (ca. 90%) and only limited renal excretion (ca. 10% of the dose). In female rats almost equal parts of the test substance were excreted with the urine (ca. 40%) and faeces (ca. 60%). 48 hours after administration, the major part of the radioactivity had been excreted (88 – 96% of the administered dose in males and females). Only a very minor part of the dose was excreted in the time range between 48 and 168 hours after administration. The expiration of ¹⁴C-carbon dioxide and other ¹⁴C-labelled volatiles was tested with animals for a test period of 48 hours. Less than 0.01% of the administered dose was expired during this sampling period in males and females.

This result is supported by the other available studies (ADME, 2005; ADME bile excretion, 2006; residue depletion and metabolism, 2006). The higher rate of biliary excretion in males was shown in the bile via cannulation (ADME bile excretion, 2006). A difference in excretion between the females administered a low and high dose, but not in the males, was observed in ‘ADME, 2005’. The renal to faecal ratio was 0.11 in low-dose males and 0.56 in low-dose females. The renal to faecal ratio was 0.20 in high-dose males and 1.79 in high-dose females. The higher renal excretion in these tests is possibly due to preferred elimination of the unchanged parent compound combined with biliary excretion of metabolites.

Reference list

ECHA (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 2.0, November 2014. European Chemicals Agency, Finland.