α-(2,4-dichlorophenyl)-1H-imidazole-1-ethanol

Endpoint summary

Description of key information

No toxicokinetic data (animal or human studies) are available on this substance.

 

Based on the moderate molecular weight (257.11 g/mol), moderate water solubility (142 mg/L), and moderate partition coefficient (log Kow 2.56), it can be expected that oral, dermal and respiratory absorption rates of T000824 are moderate to high. The adverse effects of the 28-day oral repeated dose gavage toxicity study confirm the high oral absorption rate since oral administration resulted in adverse changes of different test parameters (mortality, clinical signs, body weight, estrous cycle determination, clinical pathology, macroscopy at termination, fertility index). However, T000824 is a solid substance and therefore not readily taken up by the skin. Also, an acute dermal irritation test showed that T000824 is not irritating to skin (OECD 404, Sanders, 2006). The absorption of T000824 through inhalation is expected to be low based on the low volatility and large MMAD (>100µm). The respiratory absorption factor is therefore set to 50%. More information is provided below.

 

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

50

Additional information

T000824 is a white powder with a moderate molecular weight (257.11 g/mol), a particle size of 118.7 µm (Mass Median Diameter or MMD), a moderate water solubility (142 mg/L), a moderate partition coefficient (log Kow =2.56) and a low volatility (vapour pressure of 9.41E-08 Pa at 20°C).

The backbone of the substance is an ethanol group, with a dichlorophenyl and imidazole groups as substituent. The presence of nitrogen (aromatic amine functional groups) and alcohol group would suggest that the product has an alkaline character.

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 T000824.

Absorption

Oral/GI absorption:

T000824 is expected to be favourable for absorption based on its molecular weight of < 500 g/mol and its moderate partition coefficient (–1 < log Kow < 4). Its moderate water solubility would lead to the dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion causing absorption but only to some extent. It is generally assumed that the absorption along the gastrointestinal tract predominantly takes place in the small intestine.

An acute oral toxicity study was performed by oral gavage of T000824 to Wistar mice (OECD 420, performed in1985). Since at that moment, no data on acute toxicity were available, the first dose used in the preliminary test was 300 mg/kg bw test item in corn oil. As no evident toxicity was observed at this dose, a second animal was administered 2000 mg/kg bw test item. Based on the preliminary test results, the main experiment was performed by administering a single dose of 2000 mg/kg bw test item to four animals. Following administration, changes in body posture, locomotor activity, and bristled coat were observed in all animals. One animal died on the third day after the administration of the test item, the remaining animals survived the experiment and showed no pathological changes upon necrosis. Based on the results, the oral LD50 was found to be > 2000 mg/kg bw.

 

A combined 28-day repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422, Meijer, 2018) has been performed by gavage with T000824 on Wistar (Han) rats (40 males and 40 females) applying following doses: 30, 100 and 330 mg/kg/day (and a control group).

The parameters observed included mortality, clinical signs, functional observations and locomotor activity, body weight, food consumption, estrous cycle determination, clinical pathology, measurement of thyroid hormone T4, macroscopy at termination, organ weights and histopathology.

At 330 mg/kg bw/day there were three premature decedents, all sacrificed in moribund condition, which were considered to be test-item related. Male no. 32 and female no. 74 were euthanized at study Day 8. These animals showed clinical signs of toxicity (hunched posture, piloerection of the fur, rales, ptosis) and body weight loss (10-12% between Days 1-8). The main clinical sign of toxicity was piloerection of the fur which started after about one week of treatment and was seen most frequently in females in a dose related manner starting from the lowest dose. Less frequent findings included rales (in several males and females on a few occasions), hunched posture (in 8 out 10 females, starting on treatment Day 6 for approximately 1-2 weeks).Males and females at 330 mg/kg showed statistically significantly reduced body weight gain during the first week of treatment.

Test item-related macroscopic findings consisted of liver enlargement and accentuated lobular pattern in in males at 330 mg/kg (microscopic correlate: hepatocellular vacuolation and/or hepatocellular hypertrophy) and thickened uterus horn and/or contents (early resorptions and/or presence of dead fetuses) in females.

Microscopic examination revealed treatment-related changes in several organs such as the enlargement of the liver (330 mg/kg male), an increased severity of hyaline droplet accumulation in the kidneys (330 mg/kg male), Increased severity (up to moderate) of yellow pigmentation in the spleen (hemosiderin) in females at 30 and 100 mg/kg, changes in red blood cell parameters (100 mg/kg females and 330 mg/kg both sexes). However, these findings were considered non-adverse. The adverse microscopic changes were observed in the kidneys, lungs, adrenals, ovaries, uterus (associated with reproductive failure) of females treated at 330 mg/kg.

Reproductive toxicity was observed at 330 mg/kg as indicated by abnormalities in estrous cyclicity in most females, reduced number of implantation sites, and reduced fertility index. Developmental toxicity was observed at all doses.  

Based on the physicochemical properties and the results of the toxicity studies, theoral absorption factoris set to50%.

 

Respiratory absorption:

 

Given its low volatility (vapour pressure of 41E-08 Pa at 20°C), the availability of T000824 for inhalation as a vapour is low. There is no result available for the mass median aerodynamic diameter (MMAD) but since its MMD is larger than 100 µm, it is not expected that the solid particles have the potential to be inhaled and reach the alveolar region of the respiratory tract. 

In general, water-soluble dusts readily diffuse/dissolve into the mucus lining the respiratory tract. However, T000824 only has a moderate water solubility and the rate at which the particles dissolve into the mucus will limit the amount that could be absorbed directly when reaching the respiratory system. Moderate lipophilic substances (-1< log Kow < 4), such as T000824 also have the potential to be absorbed directly across the respiratory tract epithelium by passive diffusion.

 

Based on the physicochemical properties, the respiratory absorption factoris set to 50%.

 

 

Dermal absorption:

 

T000824 is a solid substance and therefore not readily taken up by the skinin comparison to liquid products. As the product is a solid, it will have to dissolve into the surface moisture of the skin before uptake can take place. This can be favored by the moderate water solubility of the substance but to a limited extent only.

 

It is expected that, given its lipophilic character (log Kow =2.56) the penetration of T000824 into the lipid rich environment of the stratum corneum will be favoured. Log Kow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. In the case of T000824 the dermal uptake is expected to be moderate to high since the substance might be soluble enough in water (100 mg/l < water solubility< 10,000 mg/l), to partition further from the stratum corneum into the epidermis.

 

Furthermore, T000824 is considered non-irritating to rabbit skin (OECD 404, Sanders, 2006).

As a result, the dermal absorption factor is set at 50%.

 

Distribution

T000824 only has a moderate water solubility which will limit its distribution through the body by aqueous channels and pores. However, the substance is moderately lipophilic, and could distribute into the cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues. According to the toxicological studies, the target organsmay be the liver, kidneys, lungs, adrenals, ovaries, uterus.

Accumulation

Based on the physicochemical properties of T000824 (moderate water solubility and moderate partition coeffic       ient.), no accumulation is expected within the lungs, bones or stratum corneum.

Since T000824 is a lipophilic substance, it will tend to concentrate in adipose tissue and may accumulate depending on the exposure conditions. Substances with log Kow values of 3 or less would not tend to accumulate with the repeated intermittent exposure patterns that are encountered in the workplace but may accumulate if exposures are continuous.

Metabolism

Based on the structure, T000824 might undergo phase I biotransformation reactions such as (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 T000824 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.