cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane-4-ylmethyl benzoate

Endpoint summary

Description of key information

T001095(CAS 61397-56-6) is a white powder with a moderate molecular weight (446.13 g/mol), a particle size of 12.525 µm (Mass Median Aerodynamic Diameter or MMAD), a very low water solubility (0.012 mg/L), a high partition coefficient (log Pow of 5.4-5.8 at pH 7) and a low volatility (vapour pressure of <1.4E-10 kPa at 20°C). 

No or limited dissolution of the substance in the gastrointestinal fluids is expected since it is considered insoluble in water. Based on its lipophilic character, the substance may undergo micellular solubilisation and enter the circulation through the lymphatic system. The moderate molecular weight favours absorption as well. No systemic nor acute toxicity was observed in a combined 28-day repeated dose toxicity with the reproductive/developmental toxicity screening (OECD 422) and an acute oral toxicity study (OECD 423) respectively. The oral absorption factor of T001095 is therefore set to 50%.

The respiratory absorption factor is set to 100% (conservative approach) due to its lipophilic properties and low water solubility.

The dermal absorption factor for T001095 is considered 10% based on the fact that the substance is a solid, it is considered insoluble in water and the partition coefficient is high.

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

T001095 (CAS 61397-56-6) is a white powder with a moderate molecular weight (446.13 g/mol), a particle size of 12.525 µm (Mass Median Aerodynamic Diameter or MMAD), a very low water solubility (0.012 mg/L), a high partition coefficient (log Pow of 5.4-5.8 at pH 7) and a low volatility (vapour pressure of <1.4E-10 kPa at 20°C).

The backbone of T001095 is a 3-dioxolanylmethylbenzoate group with 2 substituents at position 2 which are a 2,4-dichlorophenyl group and a bromomethyl group. The substance is not likely to ionize since it doesn’t contain acidic or alkaline groups and therefore expected to stay stable (unionized) at all pH levels.

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 T001095. 

 

Absorption

Oral/GI absorption:

T001095 is considered insoluble in water. Therefore, no or limited dissolution of the substance into the gastrointestinal fluids is expected leading to low absorption through passive diffusion. However, based on its partition coefficient (log Pow 5.4-5.8 at pH 7), the substance is expected to be lipophilic and therefore may undergo micellular solubilisation by bile salts and enter the circulation through the lymphatic system, bypassing the liver. Furthermore, its moderate molecular weight (<500) favours absorption as well.  

In an acute oral toxicity study (OECD 423; Ott, 2006), T001095 was administered via oral gavage on a single occasion to 2 subsequent groups of 3 female Wistar rats at 2000 mg/kg body weight. No mortality or abnormalities were observed at gross pathology. Slightly ruffled fur and hunched posture were observed during the first hours of observation in some animals. No adverse effects were demonstrated with LD50 established as greater than 2000 mg/kg body weight.

 

In a combined 28-day repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422; Mounier, 2017), T001095 was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 110, 330 and 1000 mg/kg body weight/day). No adverse toxicological effects were observed up to the highest dose tested (1000 mg/kg body weight/day).

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

 

Respiratory absorption:

Because T001095 has a low volatility, the availability of the powder for inhalation as a vapour is limited. Based on its low water solubility and very small particle size (12.525 µm), the substance is expected to penetrate to the alveolar region of the respiratory tract, should the substance be inhaled. Furthermore, since the substance is expected to be lipophilic, it can be taken up by micellar solubilisation. Following deposit in the alveolar region, the particles would mainly be engulfed by alveolar macrophages, which would then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. No toxicity study with administration via the inhalation route was performed.

Therefore, the respiratory absorption factor is considered 100%.

 

Dermal absorption:

Since T001095 is a solid, the product will not be readily taken up by the skin in comparison to liquid products. 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 stratum corneum.

From its partition coefficient (log Kow 5.4-5.8 at pH 7), it can be derived that the substance is rather lipophilic enhancing passage across the lipid rich environment of the stratum corneum. However, the substance is not expected to be sufficiently soluble to partition from the stratum corneum into the epidermis based on its very low water solubility (0.012 mg/L). Therefore, dermal uptake is expected to be minimal.

The substance is demonstrated to not irritate the skin based on a reliable in vivo acute dermal irritation study (OECD 404; TalviOja, 2006).

Based on the absence of dermal toxic effects in thein vivoskin irritation study and the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, no acute dermal toxicity study was conducted.

As a result, the dermal absorption factor is considered 10%.

 

Distribution

Based on its lipophilic character, T001095 is expected to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues. 

Accumulation

Since T001095 is lipophilic substance, it will tend to temporary concentrate in adipose tissue. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance. 

Metabolism

Once absorbed, T001095 might undergo phase I biotransformation such as reduction, hydroxylation and aromatic hydroxylation followed by conjugation reactions (phase II) such as glucuronidation and sulfation, largely increasing the hydrophilicity.

Excretion

The metabolites of T001095 (such as conjugated glucuronides) will most likely be excreted through the urine. Most of the metabolites will have been filtered out of the blood by the kidneys, though a small amount may enter the urine directly by passive diffusion. Furthermore, T001095 may also be actively secreted through the bile.