(4aR*, 8aR*)-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6H-benzofuro[3a,3,2-ef] [2]benzazepin-6-one hydrochloride (1:1)

Endpoint summary

Description of key information

No toxicokinetic data (animal or human studies) are available on this substance.

Based on the molecular weight (386.67 g/mol), low particle size (mass median diameter < 2.8 µm), high water solubility (36.4 g/L), very low log Kow (-2.9) and very low vapour pressure (2.25 E-11 kPa at 25°C), it can be expected that both oral and respiratory absorption rates are moderate and dermal absorption is low. The adverse effects of the 28-day oral repeated dose gavage toxicity study confirm the moderate oral absorption rate.

Distribution in the body cells is not expected to be wide based on the lipophobic character and the elimination of the product will mainly occur through the bile.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

5

Absorption rate - inhalation (%):

50

Additional information

Toxicokinetic assessment of T002102

T002102 (CAS 179108-06-6), is a powder with a moderate molecular weight (386.67 g/mol), a low particle size (mass median diameter < 2.8 µm), a high water solubility (36.4 g/L), a very low log Kow (-2.9) and a very low vapour pressure (2.25 E-11 kPa at 25°C). The substance is not found to be irritating to the skin.

The backbone of T002102 is a benzazepine group which contains a benzene ring and an azepine group (a heterocyclic ring structure with 1 nitrogen and 6 carbon atoms), substituted by a cyclohexenone and furan group, a bromine and a methoxy functional group. The structure is also hydrogenated. T002102 resembles the commercially available alkaloid called galantamine, but with a carbonyl instead of a hydroxyl functional group and a bromine attached to the benzyl group. T002102 is a racemic mixture and a hydrochloric salt.  

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physico-chemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour of T002102.

 

Absorption

Oral/GI absorption:

T002102 is a watersoluble molecule which will readily dissolve into the gastrointestinal (GI) fluids through the aqueous pores or through carriage across membranes (epithelial barrier) with the bulk passage of water (passive diffusion). The predominant site of absorption along the gastrointestinal tract is the small intestine through passive diffusion.

A 28-day repeated oral gavage toxicity study (Braun et al., 2002) has been performed with T002102. Rats were exposed to 10, 50, 200 mg/kg/day (nominal concentrations) which indicated that salivation occurred at high dose level in some males. Test substance-related findings in the clinical biochemistry parameters of males and females treated with 200 mg/kg/day (nominal concentration) indicated minor changes in lipid metabolism. Increased liver weights were observed in males and females treated with 200 mg/kg/day (nominal concentration), and test substance-related microscopic findings in the liver (minimal centrilobular hypertrophy) and thyroid gland (follicular cell hypertrophy) were noticed in males and females at 200 mg/kg/day (nominal concentration). This indicates T002102 is absorbed after oral exposure and reaches the liver and thyroid gland. The NOAEL and NOEL were considered to be 41.85 mg/kg/day (50 mg/kg/day nominal concentration corrected based on analytical verification results).

The results of a reproductive/developmental toxicity screening test of T002102 in rats by oral gavage according with dose levels of 11, 55 or 165 mg/kg/day (or 10, 50, 150 mg eq/kg/day) (Peter, 2016) revealed parental toxicity at 165 mg/kg/day in male rats (lower epididymides organ weights, histopathological changes in testes and epididymides). Reproductive toxicity was observed in female rats at 165 mg/kg/day and attributed to the adverse effect of the test item on male fertility. Furthermore, developmental toxicity was noticed at the dose level of 55 mg/kg/day.

T002102 was found to be hydrolytically stable at pH 4.0 (estimated half-life of about 200 days at 50°C), not stable at pH 7.0 (estimated half-life of 187 hours (8 days) at 25°C). For that reason, only limited degradation of the substance is expected in the gastro-intestinal tract (pH 2-8).

The oral absorption factor is set to 50%, based on the physicochemical properties and the results of the toxicity studies.

Respiratory absorption:

Given the low vapour pressure of 2.25 E-11 kPa, T002102 is not considered to be a volatile substance and the availability for inhalation as a vapour is limited. However, the product is can be considered as a dust with a mass median diameter of 2.8 µm, so inhalation is expected. There is no information on the aerodynamic diameter of the product, so no information on the deposition within the respiratory tract can be derived.

In case the substance ends up in the respiratory tract, T002102 can diffuse/dissolve into the mucus lining the respiratory tract, since it is a fine water soluble powder. However its lipophobic character implies that the product won’t be absorbed directly across the respiratory tract epithelium through passive diffusion. Based on its moderate molecular weight (MW>200), it can be predicted that the substance will not be absorbed through aqueous pores, but be retained in the mucus and transported out of the respiratory tract. However, the oral toxicity study described above (Braun et al., 2002) showed that there are signs of systemic toxicity, indicating absorption after ingestion so some absorption after inhalation can be expected. The respiratory absorption factor is set to 50%.

Dermal absorption:

T002102 is a solid substance and therefore the product is not readily taken up by the skin in comparison to liquid products. The dry product will have to dissolve into the surface moisture of the skin before uptake can take place. Based on its high water solubility (36.4 g/L) and its low log Kow value (< 0), the substance is probably too hydrophilic to cross the lipid rich environment of the stratum corneum.An acute dermal toxicity study in rats (Damme, 2001) with a fixed dose of 2000 mg/kg showed no systemic or local toxicity effects during the study period of 2 weeks. Furthermore, the product is notskin irritant or skin corrosive. Based on the physicochemical parameters and the toxicity data, it can be concluded that dermal uptake of T002102 will be low. As a result, the dermal absorption factor for T002102 is set to 5%.

Distribution

The high water solubility and moderate molecular weight predict that T002102 will probably distribute through the body due to diffusion through aqueous channels and pores. Since the substance is not lipophilic, it won’t distribute much into cells. Therefore, in fatty tissues, the extracellular concentration of the substance will be higher than the intracellular concentration. On the other hand,based on the 28-day repeated oral gavage toxicity study described above, the product distributes to the thyroid gland and liver after ingestion.

Accumulation

Since T002102 is a very water soluble and hydrophilic substance, no (or little) accumulation is expected within the body (lung, adipose tissue, stratum corneum).

Metabolism

Once absorbed, T002102 might undergo phase I biotransformation (including reduction, hydroxylation) followed byconjugation reactions (phase II) such as glucuronidation and sulfation.

Excretion

Given the moderate molecular weight (Mw>300), T002102 and its metabolites (such as conjugated glucuronides) will most likely actively be excreted through the bile. Substances in the bile pass through the intestines before they are excreted in the feces and thus may undergo enterohepatic recycling which will prolong their biological half-life.