4-[(4-HYDROXYPYRIMIDIN-2-YL)AMINO]BENZONITRILE

Endpoint summary

Description of key information

The key physicochemical characteristics of powder T002487 are: moderate molecular weight of 212.21 g/mol, a particle size of 13.369 µm ( Mass Median Aerodynamic Diameter or MMAD) and a low water solubility of 6.73 mg/L (at 20°C and pH 6.2 - 6.4). The partition coefficient was determined to be log Kow 0.9 at pH 6.6 and the vapour pressure was assessed to be < 2.1E-8 Pa at 25°C.

Considering its molecular weight (< 500 g/mol) and its moderate log Kow value between -1 and -4, oral absorption is expected but to a limited extend due to its low water solubility. No systemic toxicity was observed in a combined 28 days repeated dose toxicity with the reproductive/ developmental toxicity screening (OECD 422) up to a dose of 1000 mg/kg/day. The oral absorption factor of T002487 is therefore set to 50%.

The respiratory absorption factor is considered 100% (conservative approach) due to its small particle size.

The dermal absorption factor for T002487 is set at 50% based on its solid form, low water solubility and moderate log Kow.

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic assessment of T002487

T002487 (CAS 189956-45-4) is an off-white powder with a moderate molecular weight of 212.21 g/mol, a particle size of 13.369 µm (Mass Median Aerodynamic Diameter or MMAD), and a low water solubility of 6.73 mg/L (at 20°C and pH 6.2 - 6.4). The partition coefficient was determined to be log Kow 0.9 at pH 6.6 and the vapour pressure was assessed to be < 2.1E-8 Pa at 25°C.

The backbone of T002487 is a benzonitrile group with a 4-hydroxypyrimidin-2-ylamino group as substituent (para position). The presence of the hydroxypyrimidine would suggest that the product has a weak acidic character. This was confirmed by the theoretical calculation of the pKa value of the hydroxypyrimidine functionality which was determined to be about 8.61 (Ciric, 2016).

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 T002487.

 

Absorption

Oral/GI absorption:

T002487 has a moderate partition coefficient (–1 < log Kow < 4) and a molecular weight < 500 g/mol indicating that it is favourable for absorption. However, its low water solubility would lead to restricted dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion causing only limited absorption. It is generally assumed that the absorption along the gastrointestinal tract predominantly takes place in the small intestine since it has a very large surface area and the longest transit time.

No systemic toxicity was observed following a single dose up to 2000 mg/kg of T002487 in an acute oral toxicity study with outbred female albino mice (OECD 423, Sanders, 2004). LD50 was determined to be greater than 2000 mg/kg.

A combined 28-days repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422, van Otterdijk, 2017) has been performed by oral gavage with T002487 on Wistar (Han) rats (40 males and 40 females) applying following doses: 110, 330 and 1000 mg/kg/day (and a control group), for a duration of treatment of 28 days (males); 50-56 days (females that delivered); 41-44 days (females that failed to deliver). There was a test item-related microscopic finding in the thyroid glands and kidneys of the females of the 1000 mg/kg/day group. An increased severity of follicular cell hypertrophy of the thyroid gland up to moderate degree was noted. No toxicologically relevant changes in body weights and body weight gain were noted over the treatment period. Clinical biochemistry and haematological parameters were considered to be unaffected by treatment. In conclusion, the treatment of T002487 by oral gavage in male and female Wistar Han rats at dose levels of 110, 330 and 1000 mg/kg revealed no adverse effects on parental parameters up to the dose of 1000 mg/kg.

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

Respiratory absorption:

Given its low volatility (vapour pressure< 0.5 kPa), the availability of T002487 for inhalation as a vapour is limited. However, based on the fact that its MMAD is smaller than 15 µm, the solid particles have the potential to be inhaled and reach the alveolar region of the respiratory tract.

Since T002487 has a moderate partition coefficient (-1 < log Kow < 4), it is favorable for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low water solubility, the rate at which the particles dissolve into the mucus will limit the amount that could be absorbed directly when reaching the respiratory system. Poorly water-soluble dusts, such as T002487, depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed, while poorly water-soluble dusts depositing in the trachea-bronchial region would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed, nevertheless 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. Based on the physicochemical properties, therespiratory absorption factoris set to100%in a conservative approach.

 

Dermal absorption:

T002487 is a solid substance and therefore not readily taken up by the skin in comparison to liquid products. The product will have to dissolve into the surface moisture of the skin before uptake can take place.

It is expected that the penetration of T002487 into the lipid rich environment of the stratum corneum will be favoured to a small extent due to the limited lipophilic character (log Kow of 0.9) of the substance leading to low to moderate dermal absorption. Furthermore, based on its low water solubility (6.73 mg/L), dermal uptake is expected to be low to moderate since the substance is only slightly soluble in water to partition from the stratum corneum into the epidermis. T002487 was found to be a mild irritant (Sanders, 2004), which could enhance dermal absorption. 

As a result, the defaultdermal absorption factorfor T002487 is set to50%.

Distribution

The low water solubility will limit the distribution of T002487 through the body through aqueous channels and pores. Since the substance is expected to be rather lipophilic (log Kow of 0.9), the substance will distribute into the cells to a limited extent. Based on the toxicological studies, the target organs may be the thyroid glands and the kidneys which were affected in females at the highest dose level of 1000 mg/kg/day. Based on these observations it can be concluded that T002487 to distribute within the body to a limited extent. 

Accumulation

Based on the physicochemical properties of T002487 (low water solubility, moderate partition coefficient, etc.), no accumulation is expected within the lungs, bones or stratum corneum.

Metabolism

Based on the structure, T002487 might undergo phase I biotransformation reactions such as oxidative deamination or aromatic hydroxylation 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 water solubility and 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

The water soluble conjugated metabolites of T002487 from Phase II biotransformation will be excreted from the systemic circulation through 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 conjugated derivatives (such as glucuronides) is the bile. 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.