Benzonitrile, 4-[(4-chloro-2-pyrimidinyl)amino]-

Endpoint summary

Description of key information

The key physicochemical characteristics of the powder T002488 are: a moderate molecular weight (230.66 g/mol), low particle size (mass median diameter 6.369 μm MMAD), very low water solubility (0.839 mg/L), moderate partition coefficient (log Kow 2.8 at neutral) and low volatility (vapour pressure 8.2 E-12 kPa at 25°C). Based on its molecular weight is < 500 g/mol and its log Kow value between -1 and 4, oral absorption is expected but only to a limited extent due to its very low water solubility. The combined 28-days repeated dose oral toxicity study with the reproduction/developmental toxicity screening test confirms the low oral absorption rate as only a few changes in clinical pathology parameters were noted (but not considered adverse in absence of any morphological correlates) and no treatment-related effects on mortality, clinical appearance, functional observations, body weight, food consumption, organ weights and macroscopic appearance were observed. The respiratory absorption factor is set at 50%. Even though the aerodynamic diameter of the powder T002488 is smaller than 15 µm and the small solid (dust) particles have the potential to be inhaled and reach the alveolar region of the respiratory tract, T002488 will only to a very limited extent diffuse/dissolve into the mucus lining the respiratory tract due to its very low solubility. The dermal absorption factor for T002488 is set to 10% based on the fact that the substance is a solid, its water solubility is very low and its log Kow is moderate. Furthermore,T002488 was not considered to be an irritant substance which implies that no enhanced penetration can be caused by damage to the skin.

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

T002488 (CAS 244768-32-9) is a light brown powder with a moderate molecular weight (230.66 g/mol), a particle size of 6.369 µm (Mass Median Aerodynamic Diameter or MMAD), a very low water solubility (0.839 mg/L), a moderate partition coefficient (log Kow of 2.8 at neutral pH) and a low volatility (vapour pressure of 5.5 E-11 kPa at 25°C).

The backbone of T002488 is a benzonitrile group with a (4-chloropyrimidin-2-yl)amino group as substituent at position 4. Due to the presence of amine functionality, the substance can be considered a weak base and is ionized at low pH.

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 T002488.

 

Absorption

Oral/GI absorption:

Based on its very low water solubility, T002488 will undergo no or very limited dissolution into the gastrointestinal fluids and absorption through passive diffusion, even though its molecular weight (< 500 g/mol) and partition coefficient (between -1 and 4) favour absorption. Therefore, limited oral absorption is expected based on its physicochemical properties.

In anacute oral toxicitystudy (OECD 423; Sanders, 2004), T002488 was administered via oral gavage to female mice at dose levels 300 and 2000 mg/kg bw (stepwise procedure). No test item related effects were observed for mortality, clinical signs, body weight or macroscopic examinations. The LD50 value in female outbred albino mouse was hence determined to be greated than 2000 mg/kg bw.

A combined 28-days repeated dose oral toxicity study with the reproduction/developmental toxicity screeningtest (OECD 422; van Otterdijk, 2017) has been performed by oral gavage with T002488 on Wistar rats at the dose levels: 0, 100, 300 and 1000 mg/kg bw/day. During the study period, no adverse test item-related morphologic alterations were observed up to 1000 mg/kg bw/day. There were no adverse effects on parental parameters up to 1000 mg/kg bw/d. A microscopic finding in the thyroids (slightly increased incidence and/or severity of follicular cell hypertrophy) was considered non-adverse. A few changes in clinical pathology parameters were noted at 300 and 1000 mg/kg that were potentially related to treatment. These were not considered adverse in absence of any morphological correlates and since they essentially remained within the range considered normal for rats of this age and strain. No treatment-related effects on mortality, clinical appearance, functional observations, body weight, food consumption, organ weights and macroscopic appearance were observed.

Based on the physicochemical properties and the results of the toxicity studies, theoral absorption factoris set to50%,the default for the oral route of exposure.

 

Respiratory absorption:

Given its low volatility, the availability of T002488 for inhalation as a vapour is limited. However, based on the fact that its aerodynamic diameter is smaller than 15 µm, the small solid (dust) particles have the potential to be inhaled and reach the alveolar region of the respiratory tract where it will be engulfed by alveolar macrophages which will either translocate the particles to the ciliated airways or carry the particles to the pulmonary interstitium and lymphoid tissues.

T002488 will only to a very limited extent diffuse/dissolve into the mucus lining the respiratory tract due to its very low water solubility. Its lipophilic character (logKow>0) implies that the product has the potential to be subsequently absorbed directly across the respiratory tract epithelium through passive diffusion.

Based on the physicochemical properties, therespiratory absorption factoris set to50%.

 

Dermal absorption:

T002488 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. Based on its very low water solubility (0.839 mg/L), dermal uptake is expected to be low since the substance is expected not to be sufficiently soluble in water to partition from the stratum corneum into the epidermis.

Anacute dermal toxicitystudy (OECD 402; Latour, 2016) with Wistar rats to which a single dose of 2000 mg/kg was applied. No mortality occurred and no abnormalities were found at macroscopic post mortem examination of the animals nor in the body weight changes. The clinical signs (such as chromodacryorrhoea and white discoloration and/or scaliness) were local effects and were hence considered not to have affected the conclusion of the study.

Based on anin vivoskin irritationtest with New Zealand White rabbits (OECD 404; Sanders, 2004),T002488 was not considered to be an irritant substance which implies that no enhanced penetration can be caused by damage to the skin.

As a result, thedermal absorption factoris set to10%.

 

Distribution

Due to the low water solubility it is expected that T002488 won’t readily diffuse through aqueous channels and pores. Since the substance is lipophilic (Log Kow>0), the substance is likely to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues.

 

Accumulation

Since T002488 has a Log Kow of 2.8, accumulation is considered unlikely.

 

Metabolism

Based on the structure, T002488 might undergo phase I biotransformation such as oxidation 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 T002488 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 T002488 can be the bile. Substances excreted in the bile generally have a higher molecular weight or 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.