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EC number: 609-425-1 | CAS number: 374067-80-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
The key physicochemical characteristics of the powder T002326 are: a moderate molecular weight (228.21 g/mol), a particle size of 18.995 µm (Mass Median Aerodynamic Diameter or MMAD), a low water solubility (6 mg/L), a moderate partition coefficient (log Kow <0.3 using the HPLC method at pH7/log Kow of -0.078 using the shake flask method at pH7) and a low volatility (vapour pressure of <2.9 E-11 kPa at 25°C).
Based on its molecular weight is < 500 g/mol, its log Kow value between -1 and 4, oral absorption is expected but only to a limited extent due to its low water solubility. No systemic toxicity was observed in a combined 28 -day repeated dose toxicity with the reproductive/developmental toxicity screening (OECD 422). The oral absorption factor of T002326 is therfore set to 50%.
The respiratory absorption factor is considered 100% (conservative approach) due to its small particle size and low water solubility.
The dermal absorption factor for T002326 is set to 50% based on the fact that the substance is a solid, its water solubility is low and its logKow is moderate. Furthermore, an acute dermal toxicity study (OECD 402) showed no effects related to the test material (except for local clinical effects).
Key value for chemical safety assessment
- Absorption rate - oral (%):
- 50
- Absorption rate - dermal (%):
- 50
- Absorption rate - inhalation (%):
- 100
Additional information
Toxicokinetic assessment of T002326
T002326 (CAS 374067-80-8) is a slight beige powder with a moderate molecular weight (228.21 g/mol), a particle size of 18.995 µm (Mass Median Aerodynamic Diameter or MMAD), a low water solubility (6 mg/L), a moderate partition coefficient (log Kow <0.3 using the HPLC method at pH7/-0.078 using the shake flask method at pH7) and a low volatility (vapour pressure of <2.9 E-11 kPa at 25°C).
The backbone of T002326 is a pyrimidine group, with the following substituents: two hydroxyl groups (meta position) and an aminobenzonitrile group (meta position). The presence of nitrogen (aromatic and non-aromatic amine functional groups) would suggest that the product has a weak alkaline character. This was confirmed by the theoretical calculation of the pKavalue of the hydroxypyrimidine functionality which was determined to be about 10 (Reingruber, 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 T002326.
Absorption
Oral/GI absorption:
T002326 is considered favourable for absorption only to a limited extent based on its molecular weight of < 500 g/mol, its moderate partition coefficient (–1 < log Kow < 4) and its low water solubility leading to restricted dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion. It is generally assumed that the absorption along the gastrointestinal tract predominantly takes place in the small intestine.
No systemic toxicity was observed following a single dose up to 2000 mg/kg of T002326 in an acute oral toxicity study with outbred albino mice (OECD 423, Sanders, 2004). LD50 was determined to be greater than 2000 mg/kg.
A combined 28-day repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422, van Otterdijk, 2016) has been performed by gavage with T002326 on Wistar (Han) rats (40 males and 40 females) applying following doses: 100, 300 and 1000 mg/kg/day (and a control group). There was a test item-related non-adverse morphologic alteration in male and female thyroid gland of Wistar (Han) rats at the high dose of 1000 mg/kg/day. No test item-related morphologic alterations up to 300 mg/kg/day and no morphological findings in the reproductive organs of either sex which could be attributed to the test item were observed. There was no evidence of systemic toxicity following oral administration of T002326.
Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factor is set to50%.
Respiratory absorption:
Given its low volatility, the availability of T002326 for inhalation as a vapour is limited. However, based on the fact that its MMAD is smaller than 50 µm, the solid particles have the potential to be inhaled and reach the thoracic region.
Since T002326 is only slightly water soluble, the rate at which the particles dissolve into the mucus limits the amount that could be absorbed directly when reaching the respiratory system. Poorly water-soluble dusts, such as T002326, 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.
Furthermore, based on its moderate partition coefficient (-1 < log Kow < 4) T002326 is expected to be favourable for absorption directly across the respiratory tract epithelium by passive diffusion.
Based on the physicochemical properties, the respiratory absorption factor is set to 100% in a conservative approach.
Dermal absorption:
T002326 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 T002326 into the lipid rich environment of the stratum corneum will be limited by the poor lipophilic character of the substance leading to low dermal absorption. Furthermore, based on its low water solubility (6 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.
An acute dermal toxicity study (Latour, 2016) with Wistar rats to which a single dose of 2000 mg/kg was applied, showed no effects related to the test material except for local clinical effects at the treated skin area such as erythema maculate, scales and scabs. Based on an in vivo skin irritation test with New Zealand White rabbits (Sanders, 2004) T002326 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, the defaultdermal absorption factor for T002326 is set to 50%.
Distribution
The low water solubility will limit the distribution of T002326 through the body through aqueous channels and pores. Since the substance is expected to be poorly lipophilic, the substance will not or only to a limited extent distribute into the cells. Based on the toxicological studies, one of the target organs may be the thyroid gland which was non-adversely affected at the highest dose level. Based on these observations it can be concluded that T002326 is not likely to distribute within the body.
Accumulation
Based on the physicochemical properties of T002326 (low water solubility, moderate partition coefficient, moderate particle size, etc.), no accumulation is expected within the lungs, bones or stratum corneum.
Metabolism
Based on the structure, T002326 might undergo phase I biotransformation such as 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 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 T002326 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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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