4-bromo-2,2-diphenylbutanenitrile

Endpoint summary

Description of key information

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 T000625.

T000625 (CAS 39186-58-8) is a light yellow powder with a moderate molecular weight (300.2 g/mol), a very low water solubility (<0.01 mg/L at 20°C), a moderate to high partition coefficient (log Pow of 4.2 at pH 7) and a low volatility (vapour pressure of 1.9E-4 Pa at 20°C).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

T000625 (CAS 39186-58-8) is a light yellow powder with a moderate molecular weight (300.2 g/mol), a particle size of 25.402 µm (Mass Median Aerodynamic Diameter or MMAD), a very low water solubility (< 0.01 mg/L at 20°C), a moderate to high partition coefficient (log Pow of 4.2 at pH 7) and a low volatility (vapour pressure of 1.9E-4 Pa at 20°C).

The backbone of T000625 is a butanenitrille with 3 substituents that are a bromide and two phenyl groups. The substance is a hydrophobic salt with all its polar bond evenly distributed leading to its very low water solubility.

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 T000625.

1. Absorption

1.1 Oral/GI absorption

An acute oral toxicity study was performed according to the OECD guideline 423 (Latour, 2016, GLP) in which T000625 was administered on a single occasion by oral gavage to 2 groups of 3 female rats at 2000 mg/kg body weight. No mortality occurred. Clinical signs included hunched posture and/or piloerection noted in four out of six animals on day 1. No abnormalities were found at the macroscopic post-mortem examination of all animals.

 

A combined 28-day repeated dose oral toxicity study with the reproduction/developmental toxicity screening test (OECD 422; Pels Rijckens, 2018, GLP) has been performed by gavage with T000625 on Wistar rats administered with the following doses: 0, 50, 150 and 500 mg/kg bw/day.

The test revealed non-adverse treatment related changes in the thymus of females, in the kidneys of males and in the liver of both sexes.  No effects on the reproduction were observed but the magnitude of the retardation in growth of the pups dosed at 500 mg/kg /day was indicative of developmental toxicity. Based on these results, the following No Observed Adverse Effect Levels (NOAELs) were derived:

• Parental NOAEL: at least 500 mg/kg/day
• Reproduction NOAEL: at least 500 mg/kg/day
• Developmental NOAEL: 150 mg/kg/day (based on retardation of growth of the pups at 500 mg/kg/day during lactation)

T000625 is classified for Reproductive Toxicity Category 2.

Based on the physicochemical properties and the systemic toxicity described in these two studies, the oral absorption factor is considered to be 50%.

 

1.2 Respiratory absorption:

Because T000625 has a low volatility (vapour pressure of 1.9E-4 Pa at 20°C), the availability of the substance for inhalation as a vapour is limited. However, based on the fact that its aerodynamic diameter is smaller than 50 µm but larger than 15 µm, the solid particles have the potential to be inhaled and reach the thoracic region.

 

Since T000625 has a very low water solubility, 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 T000625, depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed. When poorly water-soluble dusts deposit in the trachea-bronchial region, they 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. T000625 is a lipophilic substance based on its moderate to high partition coefficient (log Kow slightly above 4). The product has thus the potential to be subsequently absorbed across the respiratory tract epithelium by passive diffusion.

No toxicity study with administration via the inhalation route was performed.

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

 

1.3 Dermal absorption:

T000625 is a solid and therefore will not be readily taken up by the skin in comparison to a liquid. 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 (lipid rich) stratum corneum.

The moderate to high log Kow value of 4.2 indicates that the substance is lipophilic and therefore easily crosses the lipid rich environment of the stratum corneum leading to dermal uptake.

No toxicity study via the dermal route was performed. A skin irritation study (OECD 404, Sanders 2004, non-GLP) showed that T000625 is not irritating and a skin sensitization study (OECD 429; Sanders 2004, non-GLP) indicated that it is non-sensitizing. No systemic toxicity was described in these tests.

Based on the above, a moderate dermal uptake is expected and thus the dermal absorption factor is considered 50%.

2. Distribution

The very low water solubility of T000625 will limit its distribution in the body through aqueous channels and pores. Since the substance is lipophilic, the substance is likely to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues.

3. Accumulation

Based on the physicochemical properties of T000625 (poor water solubility, moderate to high partition coefficient, moderate molecular weight), accumulation can be expected within the lungs, in the adipose tissues and stratum corneum but to a limited extent considering that the log Kow is only slightly above 4.

4. Metabolism

Based on the structure, T000625 might undergo phase I biotransformation such as hydroxylation and 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 pre-systemic (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.

5. Excretion

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 of the blood by the kidneys, but 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 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 feces and can thus undergo enterohepatic recycling which will prolong their half-life.