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Endpoint:
basic toxicokinetics, other
Remarks:
EU risk assessment
Type of information:
other: EU risk assessment
Adequacy of study:
supporting study
Reliability:
other: EU risk assessment
Rationale for reliability incl. deficiencies:
other: EU risk assessment report
Principles of method if other than guideline:
EU risk assessment report
GLP compliance:
no
Type:
other:
Results:
summary of toxicokinetic data

As cited in the EU risk assessment draft report (2007), two publications on the fate of 14C-radiolabelled CBS in rats were obviously based on the same experiment (Adachi 1989, Fukuoka 1995). In these experiments rats were given single oral doses of 250 mg/kg 14C-CBS. The amounts of radioactivity recorded from urine and from faeces were dependent on the position of the radioactivity label in the parent compound. Following administration of CBS radiolabel in the cyclohexyl moiety 14C-radioactivity was recovered to 89 % of the dose within three days. The extent of radioactivity was 65.4% in urine and 24.2% in faces. As the biliary excretion amounted to 5% it might be concluded that at least 70% of the radioactivity was observed from the gastro-intestinal tract. When the substance was 14C-labelded in the C2-position of the thiobenzothiazole, 92.3 % of the radioactivity was recovered within three days and similar amounts were found in urine (46.9%) as in faces (45%). In the urine, 2-mercaptobenzothiazol and cyclohexylamine were identified as metabolites of CBS. The results indicate intensive metabolism of CBS. As hydrolysis to 2-mercaptothiazol and cyclohexylamine will occur in the gastrointestinal tract, pre-systemic metabolism may play a role in the fate of CBS with different kinetic fate oft the metabolic breakdown products thus explaining the different recovery rate in urine and in faces with different positions of the 14C label.

The results after oral administration to rats indicate that CBS is readily absorbed and that intensive metabolism of CBS takes place. As hydrolysis to 2-mercaptobenzothiazol and cyclohexylamine may occur in the gastrointestinal tract, pre-systemic metabolism may play a role in the fate of CBS with different kinetic fate of the metabolic breakdown products. As cited in EU risk assessment draft report (2007), absorption of 100 % for the oral route is proposed to be taken for the risk characterisation and the inhalation absorption is assumed to be 100 % (default). No data are available for the dermal route. Therefore, a default value for dermal absorption should be applied. Based on the physico-chemical properties of CBS (molecular weight: 264.4 g/mol; log Pow 3.47; water solubility: 0.32 mg/l) a default value of 100 % would be derivated. However, this default value does not reflect the toxicity data (low toxicity via the dermal route). Therefore, an extent of absorption of 10 % will be assumed for dermal risk characterisation purposes.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report, which meets scientific principles
Objective of study:
toxicokinetics
Principles of method if other than guideline:
Kinetic study of acidic hydrolysis of CBS at pH 1 at 35°C
GLP compliance:
no
Species:
other: in vitro
Type:
other: Acidic hydrolysis of CBS
Results:
CBS is metabolised to MBTS in a two-step reaction
Type:
other: Acidic hydrolysis of CBS
Results:
acid hydrolysis of CBS at pH 1 is nearly constant 9% per day for the first 6 to 7 days, rapid drop down to 2% per day for the following time

Within the first 6.5 days (=156 h) the rate of hydrolysis is nearly linear with about 9.0% over day based on the CBS amount at t = 0h and than drops to about 2.0% for the following 9.5 days (= 228 h). Parallel to this pH increase per day within the first 6.5 days is about 0.4 and than suddenly drops to about 0 for the following days.

A correlation of the CBS loss with the formation of MBTS shows that at the beginning the rate of hydrolysis is remarkably higher than the rate of MBTS formation which easily be explained with the low MBT concentration in this period. When there is enough MBT present, which at pH<5 is a precipitated solid like CBS and MBTS, the MBTS formation rate increases rapidly to slow down again after 8 to 9 days (= 216 h) to nearly the same rate than that of the CBS hydrolysis. The trend of the sums of the MBT moieties of CBS and MBTS shows that within analytical accuracy all hydrolyzed CBS is metabolized to MBTS in two steps; in the beginning free mercaptobenzothiazole (MBT) and cyclohexylamine appeared. The free MBT then reacted directly with the starting substance CBS leading to dimeric MBT (mercaptobenzothiazyl disulfide, MBTS) and cyclohexylamine. The interim formed MBT was not measured as it is dissolved during work-up of the sample.

Executive summary:

Within the first 6.5 days (=156 h) the rate of hydrolysis is nearly linear with about 9.0% over day based on the CBS amount at t = 0h and than drops to about 2.0% for the following 9.5 days (= 228 h). Parallel to this pH increase per day within the first 6.5 days is about 0.4 and than suddenly drops to about 0 for the following days.

A correlation of the CBS loss with the formation of MBTS shows that at the beginning the rate of hydrolysis is remarkably higher than the rate of MBTS formation which easily be explained with the low MBT concentration in this period. When there is enough MBT present, which at pH<5 is a precipitated solid like CBS and MBTS, the MBTS formation rate increases rapidly to slow down again after 8 to 9 days (= 216 h) to nearly the same rate than that of the CBS hydrolysis. The trend of the sums of the MBT moieties of CBS and MBTS shows that within analytical accuracy all hydrolyzed CBS is metabolized to MBTS in two steps; in the beginning free mercaptobenzothiazole (MBT) and cyclohexylamine appeared. The free MBT then reacted directly with the starting substance CBS leading to dimeric MBT (mercaptobenzothiazyl disulfide, MBTS) and cyclohexylamine. The interim formed MBT was not measured as it is dissolved during work-up of the sample.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data are generally regarded as sufficient, publication written in japanese with an abstract and tables in english
Objective of study:
metabolism
Principles of method if other than guideline:
Metabolism study in rats.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14C-2 CBS
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: unspecified
Dose / conc.:
250 other: mg/kg
No. of animals per sex per dose / concentration:
no data
Type:
excretion
Results:
ca 65% and 24 % of the dose were excreted into urine and feces, respectively for 3 days after administration of labeled CBS (cyclohexyl 14C)
Type:
metabolism
Results:
cyclohexylamine and 2-mercaptobenzothiazole identified as urinary metabolites
Details on excretion:
ca 65% and 24 % of the dose were excreted into urine and feces, respectively

About 65% and 24 % of the dose were excreted into urine and feces, respectively, for 3 days after administration of labeled CBS (cyclohexyl-14C). Biliary excretion amounted to about 5% of the dose for 5 days. While about 92 % of the dose was recovered in urine and feces at a ratio of 1: 1 within 3 days when 14C-2CBS was given. Cyclohexylamine and 2 -mercaptobenzothiazole were identified as urinary metabolites.

Executive summary:

In an oral study with rats about 65% and 24 % of the dose were excreted into urine and feces, respectively, for 3 days after administration of labeled CBS. Biliary excretion amounted to about 5% of the dose for 5 days. While about 92 % of the dose was recovered in urine and feces at a ratio of 1: 1 within 3 days when 14C-2CBS was given. Cyclohexylamine and 2 -mercaptobenzothiazole were identified as urinary metabolites (Adachi 1989).

Endpoint:
basic toxicokinetics, other
Remarks:
in vivo and in vitro
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable documented publication, which meets basic scientific principles
Objective of study:
toxicokinetics
Principles of method if other than guideline:
Metabolic fates of N-oxydiethylene-2-benzothiazyl sulfenamide and N-cyclohexyl-2-benzothiazyl sulfenamide in rats were studied using tracer technique. Additionally CBS was incubated in an artificial gastric juice and degradation products determined.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14C
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Weanling male wistar rats (body weight, 200 - 230 g and about 300 g, Nippon, Bio-supp. Center, Tokyo).
Sex:
male
Route of administration:
oral: gavage
Vehicle:
DMSO
Dose / conc.:
250 other: mg/kg
No. of animals per sex per dose / concentration:
5 rats.
Type:
excretion
Results:
92.3 % of CBS recovered within 3 d: urine 46.9 %, faces 45 %, total 92%
Details on excretion:
14C-labelded in the C2-position of the thiobenzothiazole, 92.3 % of the radioactivity recovered within 3 d: urine 46.9 %, faces 45 %, total 92%

In vivo: metabolic change of CBS in the stomach: after 2 h: conversion into BTDS detected.

In vitro: incubation of CBS in artificial gastric juice: 5 min incubation: 47 % CBS, 9 % MBT, 23% BTDS; 10 min incubation: 45 % CBS, 31 % BTDS; 30 min incubation: CBS (trace), 63 % BTDS, 5 h incubation: 63 % BTDS

In vivo:

Oral administration CBS 250 mg/kg (5 rats):

Excretion %: 46.9 +/- 7.1 (urine), 45.4 +/- 15 (feaces), 92.3 +/- 16.6 (total)

Executive summary:

Metabolic fates of N-oxydiethylene-2-benzothiazyl sulfenamide and N-cyclohexyl-2-benzothiazyl sulfenamide in rats were studied using tracer technique. These compounds given orally to rats were excreted rapidly in the urine and feces. Five urinary metabolites, 2-mercaptobenzothiazoIe (MBT), its three conjugates, mercapturate, glucuronide and sulfate, and 2,2 -dibenzothiazyl disulfide (BTDS) were confirmed.

Furthermore, BTDS was found as a fecal metabolite. The sulfenamides were partly transformed in the stomach to BTDS, which was predominantly excreted into the feces. In the liver, the sulfenamides were mainly transformed to MBT and its conjugates. The 5-glucuronide and 5-sulfate conjugates were predominantly excreted into the bile.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable documented publication, which meets basic scientific principles
Principles of method if other than guideline:
Analytic
GLP compliance:
no
Type:
metabolism
Results:
CBS can undergo hydrolysis to 2 -mercaptobenzothiazole (MBT) and MBTS (2,2'-benzothiazyl disulfide) at pH 6.5
Metabolites identified:
yes
Details on metabolites:
2 -mercaptobenzothiazole (MBT) and MBTS (2,2'-benzothiazyl disulfide).

Detection: CBS can undergo hydrolysis to 2-mercaptobenzothiazole (MBT) and MBTS (2,2'-benzothiazyl disulfide).

CBS showed instability in buffer solution at pH 6.5. After 2 h, 2/3 of the original CBS amount were recorded, but only small amount was converted into MBTS and even less 2-MBT was found. When 1 µmol CBS and 1 µmol 2-MBT were mixed together in buffer solution at pH 6.5 and analysed after 15 min, 0.5 µmol of 2-MBT was found but only 0.3 µmol of CBS. MBTS was found in an amount of 0.6 µmol. In the presence of excess glutathione, CBS laregly disappeared within 10 min, and most of it was present as 2-MBT. After 1 h reaction time, all CBS had disappeared and was found as 2-MBT. Faster formation of 2-MBT from CBS took place when cysteine was used as sulhydryl compound instead of glutathione.

Executive summary:

CBS can undergo hydrolysis to 2 -mercaptobenzothiazole (MBT) and MBTS (2,2'-benzothiazyl disulfide).

Description of key information


  • Hydrolysis nearly linear for first 6.5 days - non TG -in-vitro hydrolysis study - Lanxess (2007)

  • Cyclohexylamine and 2 -mercaptobenzothiazole were identified as urinary metabolites – non TG metabolism study – unspecified oral route – Adachi (1989)

  • Five urinary metabolites, 2-mercaptobenzothiazoIe (MBT), its three conjugates, mercapturate, glucuronide and sulfate, and 2,2 -dibenzothiazyl disulfide (BTDS) (also in faeces) were confirmed – non TG toxicokinetics study – gavage – Fukuoka (1995)

  • CBS can undergo hydrolysis to MBT and MBTS - non TG quantification study - HPLC - Hansson (1993)

  • CBS is readily absorbed and intensive metabolism of CBS takes place - TG - toxicokinetic risk assessment - EU risk assessment (2008)

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

Experimental Data:


As cited in the EU risk assessment report (2008), two publications on the fate of 14C-radiolabelled CBS in rats were obviously based on the same experiment (Adachi 1989, Fukuoka 1995). In these experiments rats were given single oral doses of 250 mg/kg 14C-CBS. The amounts of radioactivity recorded from urine and from faeces were dependent on the position of the radioactivity label in the parent compound. Following administration of CBS radiolabel in the cyclohexyl moiety 14C-radioactivity was recovered to 89 % of the dose within three days. The extent of radioactivity was 65.4% in urine and 24.2% in faces. As the biliary excretion amounted to 5.0 % it might be concluded that at least 70% of the radioactivity was observed from the gastro-intestinal tract. When the substance was 14C-labelded in the C2-position of the thiobenzothiazole, 92.3 % of the radioactivity was recovered within three days and similar amounts were found in urine (46.9 %) as in faces (45.0 %). In the urine, 2-mercaptobenzothiazol and cyclohexylamine were identified as metabolites of CBS. The results indicate intensive metabolism of CBS. As hydrolysis to 2-mercaptothiazol and cyclohexylamine will occur in the gastrointestinal tract, pre-systemic metabolism may play a role in the fate of CBS with different kinetic fate of the metabolic breakdown products thus explaining the different recovery rate in urine and in faces with different positions of the 14C label. 


In a more recent study, the acid hydrolysis of CBS at pH1 and 35 °C was evaluated in vitro. The study shows that CBS exerts a hydrolysis rate of 9 % per day at pH 1 and 35 °C for the first 6 to 7 days followed a drop to 2 % until the end of the study on day 16. The study of the hydrolysis products done in parallel showed that in the beginning free 2-mercaptobenzothiazole and cyclohexylamine appeared. The free 2-mercaptobenzothiazole than reacted directly with the starting substance CBS leading to dimeric 2-mercaptobenzothiazole (mercaptobenzothiazol-2-yl disulfide) and cylohexylamine.


Acute oral toxicity is low with LD50 values >5000 mg/kg bw. Dermal toxicity in rabbits is very low (LD50 >5000 mg/ kg bw) (Monsanto, 1973). Clinical signs noted in the acute dermal toxicity test included reduced appetite and activity for 3 to 5 days. Studies with repeated oral dosing of rats indicating bioavailability of the compound by showing dose related toxic effects (MHJW, 1997). Inhalation toxicity was assessed repeat dose, however as the particle size recommended in guidance was not observed, the relevant regions of the respiratory tract may not have been reached (Monsanto, 1981). The subacute dermal toxicity study performed in rabbits showed no systemic or local effects up to 2000 mg/kg bw and day (Monsanto, 1981). (See chapter repeated dose toxicity).


ADME


Absorption - Oral/G.I.


The structure of CBS contains several functional groups which may lead to electrophilic/nucleophilic attack which could lead to the evolution of ionizable groups. However due to the sulphane bonding between the benzothiazole moiety and the other secondary amine moieties in CBS, there is a stabilizing effect which will diminish the likelihood of these interactions as opposed to for example BT. Therefore, for the parent substance, ionisation is unlikely to affect absorption.


CBS is readily absorbed due the molecular weight being below 500 (CBS MW is 264.4). CBS is hydrolysed and has a half-life of 13.9 hours and due to the rapid hydrolysis of CBS, it is likely that some toxicity is a result of exposure to degradants. CBS hydrolyses to 2-mercaptobenzothiazole (MBT) and cyclohexylamine (CHA) (Adachi 1989, Hansson 1993, Lanxess 2007). However, the absorption and behaviour of the parent compound can still play a significant role in the toxicokinetics of the substance as it will still remains at 50 % or greater for greater than half a day. Hence, there is time for absorption, distribution, metabolism and possibly excretion prior to full hydrolysis of the substance. The drivers of toxicity will be explored later, and regardless of parent toxicokinetics, the metabolites may still be the drivers.


The particle size distribution of CBS was determined and the median diameter was 27 µm with the main fraction of 93 % distributing in the range of 10 to 100 µm (Currenta, 2010); and hence the tested CBS particles with sieved size smaller than 100 µm are mainly dominated by inhalable fraction as defined in EN 481/ISO 7708 (1995). CBS has a log P value of 5.02 and low water solubility (0.32 mg/l at 21°C, Monsanto, 1980). For lipophilic substances may micellular solubilisation may be an important mechanism for absorption and the mechanism is of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed (ECHA R.7c, 2017). The molecular size is not below 200 Da, and as such carriage through the epithelial barrier by the bulk passage of water is less likely. In an acute oral toxicity study with corn oil as the vehicle and in the repeat dose toxicity study with sesame oil as a vehicle performed in the rat, CBS was readily absorbed. This is despite the possible slowing down of absorption that oil based vehicles can cause. Which was not an issue here. The results of the acute oral toxicity (Monsanto, 1973), repeated dose oral toxicity (MHJW, 1997) and ADME studies performed in the rat (Adachi, 1989 and Fukuoka, 1995), suggest that CBS is absorbed from the gastro-intestinal tract and CBS undergoes extensive metabolism. This supports the aforementioned absorption processes. See Table 8, for all toxicological responses and studies.


Absorption – Respiratory/inhalation


CBS has a vapour pressure of 0.0000453 Pa at 25 °C (Monsanto, 1980) and is decomposed at 145 °C (Bayer AG, 1997) and this means that CBS has low volatility when in a solvent and is not readily available as a vapour. The particle size was 93 % in the range of 10-100 µm which means that CBS may have the ability to be inhaled and potentially reach the thoracic and alveolar regions in humans (ISO 7708:1995, 2017). CBS may have the potential to be absorbed in the lower respiratory tract. CBS is poorly soluble (0.32 mg/L) thus this will limit the amount of the substance that can be absorbed directly via dissolution in mucus. Poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed (Schlesinger, 1995). It may be that considering the size that the particles reach the tracheo-bronchial region and would mainly be cleared from the lungs by the mucociliary mechanism and swallowed. However, a small amount may be taken up by phagocytosis and transported to the blood via the lymphatic system. A fraction of the particle below 15 µm may reach the alveolar region where they would mainly be engulfed by alveolar macrophages and either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. The inhalation toxicity of CBS was examined in a subacute inhalation study (Monsanto, 1981). The study is limited concerning the recommended particle-size distribution given as aerosols with mass median aerodynamic diameters (MMAD) ranging from 1 to 3 µm are recommended. The MMAD used in this study was above the recommendations given (7.6 µm) in current guidelines and thus an exposure of all relevant regions of the respiratory tract might not have been given. The biological relevance of sporadic findings reported, especially systemic effects are questionable due to a lack of monotonic dose dependence with effects.  However, increase in aspartate aminotransferase indicate distribution tot he liver (i.e. after absorption) and effects on the lymph nodes also align with the assumptions noted above that the particle can be absorbed in the alveolar regions. Based on the fact that signs of nasal irritation observed at clinical examination were reversible, only short in duration and could not be correlated to histopathological effects, no toxicological significance was attached to this finding and thus, no relevant local effects were observed up to 0.048 mg/L.


Absorption – Dermal


In particulate form CBS is likely to be absorbed to a lesser degree than when dissolved or co-administered with a vehicle. The molecular weight is between 100 to 500 Da, so based on molecule size only moderate absorption might be expected.  As discussed, though some ionisable groups are present on the parent compound, these are unlikely to ionise due to the stabilising effects of the chemical structure and stearic hinderance. So no slowing of uptake due to this is expected. The water solubility (0.32 mg/L) suggests low absorption by the epidermis with a log P that also suggests limited rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum as high (log P value is between > 4 < 6). Surface tension is not a desired property and the vapour pressure i slow, increasing contact time with the skin should exposure be present. There are no trace elements present in CBS. Based on the physical-chemical parameters alone, absorption will be low to moderate.


CBS was applied as a suspension in corn oil in an acute dermal toxicity study (Monsanto, 1973) and applied as a neat powder which was moistened in a subacute dermal repeat dose study (Monsanto, 1981) both studies were performed in the rabbit. The acute dermal toxicity of the test substance CBS was evaluated in an acute dermal toxicity study with New Zealand albino rabbits (Monsanto 1973). No mortality occurred. The dermal LD50 for the test substance CBS was greater than 7940 mg/kg bw. The results of the acute toxicity is not acutely toxic via this route.  The subacute dermal toxicity study showed CBS is not significantly toxic via this route during repeat exposure, though there was evidence of local toxicity. The skin sensitisation results of human patch tests (Monsanto, 1982) and a guinea pig maximisation test (Monsanto, 1982) show that the test material (or a product of hydrolysis, 2-mercaptobenzothiazole and cyclohexylamine) is absorbed through the skin, as the substance is noted as a skin sensitiser. CBS is known to break down into MBT which leads to skin sensitisation effects by reaction with skin protein molecules, via nucleophilic substitution (SN2) to form disulphide bridge between skin proteins and the benzothiazole moiety, as observed in papers by American Chemistry Council (2003) and Adams (2006). The studies show that the substance is absorbed but perhaps at a low level where systemic effects are unable to occur, however, skin sensitisation does occur showing there is sufficient absorption for this effect of the parent or hydrolysis products is occurring.


Distribution


The small molecular size of CBS means that wide distribution is possible. It may to some degree diffuse through aqueous channels and pores due its water solubility, though this is likely limited. The MBS log P value is over P > 0 and therefore it is likely to distribute into cells and the concentration has the potential to be higher intracellularly as opposed to extracellularly, this is particularly in regard to fatty tissues. Based on the existing in vivo data, the target organ of concern for CBS is the kidneys although the findings were reversible after a 14-day recovery period (MHJW, 1997). There are also impacts on reproductive function showing possible distribution to these areas. The results of the oral repeated dose studies performed in the rat show systemic distribution. The positive sensitisation response observed in the human repeat insult patch test suggests that the hydrolysis products may bind to circulatory proteins. The inhalation study also shows that the substance is able to reach other organs and the areas of the lymphatic system. Though no dose-dependent responses were observed. The studies support that there is wide distribution of CBS after exposure.


Metabolism


The widespread distribution throughout tissues, and the tendency of CBS to undergo hydrolysis in the gastrointestinal tract show that pre-systemic metabolism may play a role in the fate of CBS with different kinetic fate of the metabolic breakdown products. This was shown in the study by Fukuoka (1995) where following administration of CBS radiolabelled in the cyclohexyl moiety, 89 % of the dose within three days. The extent of radioactivity was 65.4% in urine and 24.2% in faeces. When the substance was 14C-labelded in the C2-position of the thiobenzothiazole, 92.3 % of the radioactivity was recovered within three days and with  46.9 % found in the urine and 45 % in the faeces.  In the urine, MBT and cyclohexylamine were identified as metabolites of CBS.  This corroborates with findings for MBS where the main metabolites were MBT and the substituent oft he parent that was attached to it. This shows that metabolism and cleavage at the thiol group is consistent across category members. The results in the OECD QSAR toolbox (v4.5) also show these metabolites (Appendix XX). The results following oral intake of CBS indicates intensive metabolism and it was transformed into MBT and cyclohexylamine (Adachi 1989, Fukuoka 1995, Hansson 1993, Lanxess 2007) prior to excretion in the urine or faeces.


Excretion


After oral administration the radioactivity relative to dose was 65.4% in urine and 24.2% in faeces. When the substance was 14C-labelded in the C2-position of the thiobenzothiazole, 92.3 % of the radioactivity was recovered within three days and with 46.9 % found in the urine and 45 % in the faeces.  Due to its presence in bile, CBS may also undergo enterohepatic circulation prior to excretion. There was no evidence found in the studies that suggested CBS is found at higher concentrations in breast milk than in blood/plasma. CBS does not excrete into the hair or nails. Mucus from the lungs would be cleared and excreted or swallowed and undergo the same processes as if administered orally.


Potential for accumulation


Based on the information provided from the log P value of ca. 5 it is possible that CBS may accumulate. However, due to its extensive metabolism and subsequent excretion, the accumulation potential is thought to be low.  Particles are > 1 µm and thus, accumulation in the lungs may be less likely. The log P is > 4 < 6 so it is possible that the parent substance may accumulate in the stratum corneum, however, due to the metabolism and hydrolysis expected, and the fact that the metabolites and hydrolysis products have log P values less than 3, accumulation here is unlikely.


 


A summary of the available study data and desk based toxicokinetic assessment is provided below. This substance is part of a category; please refer to section 13.2 for further information.