N-cyclohexylcyclohexanamine 2-[1-[[[(1R)-1-[3-[(1E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: predictions from Basic Data set

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A qualitative assessment of the toxicokinetics of the substance has been performed, based upon its physical properties and the results of toxicological studies.

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

other: Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance Version 2.0 November 2014

GLP compliance:

no

Radiolabelling:

no

Species:

other:

Bioaccessibility (or Bioavailability) testing results:

key physical properties:

Molecular weight: 767.5 comprising of Montelukast (586.2 Da) and Dicyclohexylamine (181.3 Da)
Water solubility: The flask method was applied for the determination of the water solubility of Montelukast Dicyclohexylamine Salt. The water solubility of the test substance at 20°C based on Dicyclohexylamine was 0.0464 g/l. The water solubility of the test substance at 20°C based on Montelukast was ≤ 0.5 mg/l. The pH of the aqueous samples was 6.4 – 8.3.
Partition co-efficient (log Pow): One key study was completed for partition coefficient according to EC A.8 and OECD method 107 following GLP.  As the substance is a salt a log Pow value was determined for the cationic and anioic portion of the substance. Based on Dicyclohexylamine the log Pow Value is 0.2 and based on Montelukast the log Pow  is 4.9 at 20°C by the shake flask method.
Particle size: From the particle size distribution 2.02 % of particles have a diameter of less than or equal to 10µm (respirable fraction);
6.3% of particles have a diameter of less than or equal to 30µm (Thoracic fraction); 25%
of particles have a diameter of less than or equal to 100µm (Inhalable fraction).
Dissociation constant: not determined
Hydrolysis: not determined
Structural alerts- The substance comprises of a salt of dicyclohexylamine and montelukast acid. The substance can be expected to dissociate in physiological fluids to its component ions. Systemic effects have been predicted on the results of studies conducted on the consituent ions.

acute oral toxicity: discriminating dose 2000mg/kg bw

acute dermal toxicity: discriminating dose 2000 mg/kg bw

repeat dose oral toxicity: The registered substance comprises of two component ions which can be expected to dissociate into their respective species following oral administration and exposure to gastric fluids;

systemic effects were observed in repeat dose toxicity studies conducted on the constituent ions, DCHA and Montelukast

Reproductive toxicity: The chemical species have been examined in separate reproductive screening studies which resulted in NOAEL of 40 mg/kg bw/day and 100 mg/kg bw/day for DCHA and Montelukast respectively.

skin exposure- non irritant and non-sensitising

eye exposure- non-irritant

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Oral: evidence presented by the repeat dose and reproductive toxicity studies indicates that the substance is absorbed following administration in aqueous or non-aqueous vehicles; this is despite of the very low water solubilities of the constituent ions (46.4 mg/l DCHA; ≤ 0.5 mg/l Montelukast) and lipophilic partition co-efficient (DCHA 0.2; Montelukast 4.9). Fetal/embronic effects (decreased weight gain) also indicate that the substances are readily distributed once absorbed.

Inhalation: Particle size (<45µm) would indicate that the substance is respirable- the low water solubility will enhance the penetration to the lower
respiratory tract. Given that oral absorption of the substance has been demonstrated in the 28 repeat dose study, it can be expected that absorption by the inhalation route is also likely.
Dermal absorption: based upon the physical properties of molecular weight, water solubility and partition coefficient- dermal uptake is expected to be low.

Metabolism: Studies in rats indicate that hepatic metabolism (EFCOD) is not induced by exposure to Montelukast; in vitro studies with liver slices/homogenates indicate that DCHA is not subject to hepatic metabolism.

Excretion: Following oral dosing in rabbits, Significant amounts of DCHA (27-44%) are excreted unmodified within 72 hours. 86% of montelukast is eliminated in faeces with <0.2% excreted in the urine.

Executive summary:

Based upon the results of repeat dose toxicity testing and the physical properties of the substance, it can be predicted that absorption and distribution can be expected by the oral route; a default value of 50% bioavailability is assigned for this route.

Uptake is unlikely by the dermal route, a default value of 10% is assigned based upon the physical properties of the substance.

Based on the particle size distribution, only 6% of the registered substance would reach the lungs, with 25% being available

through oral/inhalation routes, therefore a value of 25% bioavailability by the inhalation route is justified.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

25