4-[(6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile

Endpoint summary

Description of key information

T002615 (CAS 1070377-34-2) is characterized as a white, light brown powder having a moderate molecular weight (375.82 g/mol), a very low water solubility (< 0.5 mg/L), a moderate partition coefficient (log Pow of 3.9 at 25°C), a mean mass diameter of 15.8 µm and a low volatility (vapour pressure of 4.72E-10 Pa at 25°C).

T002615 is considered insoluble in water. Therefore, no or limited dissolution of the substance into the gastrointestinal fluids is expected leading to low absorption through passive diffusion.

In a 28-day oral toxicity (gavage) study according to OECD guideline 407, no treatment-related adverse toxicological effects were observed up to the highest dose tested. Furthermore, in an acute oral toxicity study performed according to the OECD guideline 423, the LD50 was established as greater than 2000 mg/kg. No acute oral toxicity is expected.

Therefore, the oral absorption factor is assumed to be 50%.

T002615 can be considered as a poorly water-soluble dust. Since T002615 has a moderate partition coefficient, it is expected to be favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Therefore, the respiratory absorption factor is considered 100%.

T002615 is rather lipophilic enhancing passage across the lipid rich environment of the stratum corneum. However, the substance is not expected to be sufficiently soluble to partition from the stratum corneum into the epidermis based on its low water solubility. Therefore, dermal uptake is expected to be minimal. Furthermore, an acute dermal study showed no indications of dermal toxicity. The dermal absorption factor is set to 10%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic assessment of T002615

T002615 (CAS 1070377-34-2) is a white, light brown powder with a moderate molecular weight (375.82 g/mol), a very low water solubility (< 0.5 mg/L), a moderate partition coefficient (log Pow of 3.9 at 25°C), a mean mass diameter of 15.8 µm and a low volatility (vapour pressure of 4.72E-10 Pa at 25°C).

The backbone of T002615 is a pyrimidine group with a cyanophenylamino group attached at position 2 (between the 2 nitrogen atoms), a 3,5-dimethylbenzonitrile-4-oxy group at position 4 and a chlorine at position 6. T002615 does not contain strong acidic or basic groups. This was confirmed by the water solubility study (Tognucci, 2003) where the pH value of T002615 in water was determined to be between 6.22 and 7.31.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physicochemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour of T002615.

Absorption

Oral/GI absorption:

T002615 is considered insoluble in water. Therefore, no or limited dissolution of the substance into the gastrointestinal fluids is expected leading to low absorption through passive diffusion. However, based on its partition coefficient (log Pow 3.9 at 25°C), the substance is expected to be lipophilic and therefore may undergo micellular solubilisation by bile salts and enter the circulation through the lymphatic system, bypassing the liver. Furthermore, its moderate molecular weight (<500) favours absorption as well.

In a 28-day oral toxicity (gavage) study according to OECD guideline 407 (RCC, 2003), T002615 was administered by daily oral gavage to male and female SPF-bred Wistar rats at dose levels of 0, 50, 200 and 1000 mg/kg body weight/day for 28 days. No treatment-related adverse toxicological effects were observed up to the highest dose tested. Based on the results of this study (no effects on mortality, clinical signs, mean absolute or relative food consumption, mean absolute body weights or body weight gain, parameters of hematology or clinical biochemistry, and mean organ weights, organ-to-body weight or organ-to-brain weight ratios), 50 mg/kg bw/day of T002615 was established as the no-observed-effect-level (NOEL) and >=1000 mg/kg bw/day of T002615 as the no-observed-adverse-effect-level (NOAEL).

An acute oral toxicity study was performed according to the OECD guideline 423 (RCC, 2003) in which T002615 was administered on a single occasion by oral gavage to 2 subsequent groups of 3 female and 3 male Wistar rats at 2000 mg/kg body weight. Slightly ruffled fur and hunched posture was noted in all 2000 mg/kg treated female animals one hour after the treatment. No clinical signs were observed in the male animals during the course of the study. These signs demonstrated to be reversible; the LD50 was established as greater than 2000 mg/kg. No acute oral toxicity is expected.

In a reproduction/developmental toxicity screening test of T002615 in rats by oral gavage according to OECD guideline 421 (Charles River, 2017), T002615 was administered by daily oral gavage to male and female SPF-bred Wistar rats (10 animals/sex/dose) at dose levels of 0, 50, 200 and 1000 mg/kg body weight/day. No parental, reproduction nor developmental toxicity was observed up to 1000 mg/kg/day.

Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factor is considered 50%.

 

Respiratory absorption:

Because T002615 has a low volatility, the availability of the powder for inhalation as a vapour is limited. Based on the very low water solubility and the fact that its mean mass diameter was determined to be 15.8 µm according to the laser diffraction method (Tognucci, 2003), T002615 can be considered as a poorly water-soluble dust. The rate at which the particles dissolve into the mucus will limit the amount that can be absorbed directly. Poorly water soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out or swallowed, while depositing in the trachea-bronchial region they would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed. Though, a small amount can be taken up by phagocytosis and transported to the blood through the lymphatic system. Poorly water-soluble dusts depositing in the alveolar region would mainly be engulfed by alveolar macrophages which will either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues.

Furthermore, since T002615 has a moderate partition coefficient, it is expected to be favourable for absorption directly across the respiratory tract epithelium by passive diffusion (micellular solubilisation). No toxicity study with administration via the inhalation route was performed.

Therefore, the respiratory absorption factor is considered 100% in a conservative approach.

Dermal absorption:

Since T002615 is a solid, the product will not be 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. In order to cross the skin, the compound must first penetrate into the stratum corneum. From its partition coefficient, it can be derived that the substance is rather lipophilic enhancing passage across the lipid rich environment of the stratum corneum. However, the substance is not expected to be sufficiently soluble to partition from the stratum corneum into the epidermis based on its low water solubility. Therefore, dermal uptake is expected to be minimal.

An acute dermal toxicity study according to OECD guideline 402 (RCC, 2003) where 2000 mg/kg of T002615 was applied to 5 male and 5 female Wistar rats, demonstrated no indications of dermal toxicity. Furthermore, based on an in vivo skin irritation study with New Zealand White rabbits according to OECD guideline 404 (RCC, 2003), the substance is demonstrated to not irritate the skin and therefore not enhancing dermal absorption.

As a result, the dermal absorption factor is considered 10%.

Distribution

Based on its lipophilic character, T002615is expected to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues. 

Accumulation

Since T002615 is a lipophilic substance, it will tend to temporary concentrate in adipose tissue. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance. In case fat reserves are mobilized more rapidly than normal (stress situation or during lactation there is the potential for large quantities of the parent compound to be released into the blood. In addition, the substance may persist in the stratum corneum, but will eventually be cleared as the stratum corneum is sloughed off.

Metabolism

Based on the structure, T002615 might undergo phase I biotransformation such as aromatic hydroxylation or oxidative deamination followed by conjugation reactions (phase II) such as glucuronidation (by the enzyme glucuronosyltransferase) and sulfation (by the enzyme sulfotransferase). The Phase II conjugation reactions largely increase the hydrophilic character of the product. Metabolism mainly takes place in the liver, causing route specific presystemic (or first pass) effects, especially after oral intake. Other metabolic changes may take place in the gastrointestinal (GI) flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

Excretion

A possible route of excretion of T002615 from the systemic circulation is the urine. In general, conjugated metabolites such as glucuronides and sulfates from Phase II biotransformation reactions, which are more water soluble than the parent compound, are excreted in the urine. Most of them will have been filtered out from the blood by the kidneys, though a small amount can enter the urine directly by passive diffusion. There is also the potential for re-absorption into the systemic circulation across the tubular epithelium. Another route of excretion of T002615 can be the bile. Substances excreted in the bile may be conjugated (such as glucuronides). The excretion via the bile is highly influenced by hepatic function since metabolites formed in the liver may be excreted directly into the bile without entering the bloodstream. Products in the bile pass through the intestine before excretion in the faeces and can thus undergo enterohepatic recycling which will prolong their half-life.

As indicated above, due to its lipophilic character passage across the lipid rich environment of the stratum corneum of the skin is enhanced. However, the substance is not expected to be sufficiently soluble to partition from the stratum corneum into the epidermis based on its low water solubility. T002615 that has penetrated the stratum corneum (but not the viable epidermis) will be sloughed off with skin cells through exfoliation.

Another route of excretion can be saliva (excretion of the non-ionized and lipid soluble T002615) which may be swallowed again or the sweat.