.alpha.-D-Glucopyranosyl bromide, 2,3,4,6-tetrakis(2,2-dimethylpropanoate)

Endpoint summary

Description of key information

T003421 (CAS 81058-27-7) is a white, crystalline powder with a moderate molecular weight (579.53 g/mol), a very low water solubility (< 0.02 mg/L at 20°C and pH 8.0-8.3), a high partition coefficient (log Pow of > 7.2 at pH 7), a low volatility (vapour pressure of 8.3E-7 Pa at 20°C and 1.1E-6 Pa at 25°C) and a particle size of 4.285 µm (Mass Median Aerodynamic Diameter or MMAD). No toxicokinetic data (animal or human studies) are available on this substance. The data presented in this dossier are based on physicochemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour of T003421.

Key value for chemical safety assessment

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

T003421 (CAS 81058-27-7) is a white, crystalline powder with a moderate molecular weight (579.53 g/mol), a very low water solubility (< 0.02 mg/L at 20°C and pH 8.0-8.3), a high partition coefficient (log Pow of > 7.2 at pH 7), a low volatility (vapour pressure of 8.3E-7 Pa at 20°C and 1.1E-6 Pa at 25°C) and a particle size of 4.285 µm (Mass Median Aerodynamic Diameter or MMAD).

Based on a study on the dissociation constant (OECD112; Ciric, 2017), T003421 has no pKa values for acidic and basic groups in the logarithm range of 1 – 14.

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 T003421.

 

Absorption

Oral/GI absorption:

Absorption of T003421 is not considered to be likely to occur given its high partition coefficient (log Pow > 7.2), very low water solubility (< 0.02 mg/L) and moderate molecular weight > 500 g/mol. These parameters taken together suggest that the absorption of a highly lipophilic substance like T003421 may be limited by their inability to dissolve into GI fluids and hence lesser contact with the mucosal surface. However, its absorption will be enhanced if it undergoes micellular solubilization by bile salts. T003421 is then likely to enter the circulation via the lymphatic system, by passing the liver.

An acute oral toxicity study was performed according to the OECD guideline 423 (Latour, 2016) in which T003421 was administered on a single occasion by oral gavage to 2 subsequent groups of 3 female Wistar rats at 2000 mg/kg body weight. Uncoordinated movements, piloerection and/or hunched posture were noted for five animals on Day 1. The mean body weight gain shown by the surviving animals over the study period was considered similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of all animals. No mortality occurred. The LD50 (female rat) was established as greater than 2000 mg/kg.

In a combined 28-day repeated dose toxicity study with the reproductive/developmental toxicity screening test (OECD 422; van Otterdijk, 2018), T003421 was administered by daily oral gavage to male and female Wistar rats at dose levels of 0, 80, 250 and 750 mg/kg body weight/day for 29 days (males) or up to 62 days (females). The study revealed no parental toxicity up to the highest dose tested (750 mg/kg). Therefore, a No Observed Adverse Effect Level (NOAEL) of 750 mg/kg was derived.

In a 90-day study (OECD 408; Lourens, 2022), T003421 was administered daily via oral gavage to male and female Wistar Han rats at dose levels of 110, 330 and 1000 mg/kg/day (10 rats/sex/group). There were no premature deaths in this study. No test item-related and toxicologically relevant changes were noted in any of the parameters investigated (i.e. clinical observations, body weight, food consumption, functional observations, ophthalmoscopy, clinical pathology investigations (i.e., hematology, coagulation and clinical chemistry parameters), and pathological examinations (i.e., organ weight changes, necropsy or microscopic findings). The NOAEL was established as at least 1000 mg/kg/day.

In a prenatal development toxicity study (OECD414; Bressers, 2022), time-mated female Wistar Han rats were treated with the test item from Day 6 to 20 post-coitum inclusive, by daily oral gavage at dose levels of 110, 330 and 1000 mg/kg/day. The following parameters and end points were evaluated in this study for the F0-generation: mortality/moribundity, clinical signs, body weights, food consumption, thyroid hormone levels (triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH)), macroscopic examination, organ weights (thyroid gland), uterine contents, microscopic examination (thyroid gland), corpora lutea, implantation sites and pre- and post-implantation loss. For the F1-generation the evaluated parameters were: the number of live and dead fetuses, fetal body weights, sex ratio, anogenital distance, external, visceral and skeletal malformations and developmental variations. No maternal toxicity and no developmental toxicity was observed at any of the tested doses and, in conclusion, the maternal and developmental NOAELs were considered at least 1000 mg/kg/day.

Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factor is considered 10%.

 

Respiratory absorption:

Because T003421 has a low volatility, the availability of the substance for inhalation as a vapour is limited. However, because its MMAD is smaller than 50 µm (4.285 µm), the solid particles can be considered as a dust and thus have the potential to be inhaled and reach the thoracic region. Its lipophilic character implies that the product has the potential to be subsequently absorbed across the respiratory tract epithelium by passive diffusion. However, the very low water solubility and the molecular weight higher than 500 g/mol will cause the substance to be retained within the mucus and transported out of the respiratory tract rather than being absorbed after inhalation. No toxicity study with administration via the inhalation route was performed.

Therefore, the respiratory absorption factor is considered 50%.

 

Dermal absorption:

Since T003421 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 (lipid rich) stratum corneum.

The highly lipophilic character of T003421 is a favorable factor for the substance to cross the stratum corneum, which consists of non-viable 4 layer of corneocytes forming a complex lipid membrane. However, based on its very low water solubility and its Log Pow > 7, the rate of transfer of T003421 between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake of T003421 into the stratum corneum itself may be slow.

No acute dermal toxicity was conducted since the physicochemical and toxicological properties suggest no potential for a significant rate of absorption through the skin.

Furthermore, the substance is not irritating to skin based on an in vitro skin irritation study (OECD guideline 439; Eurlings, 2016).

As supporting information indicating limited absorption via the dermal route, a log Kow > 6 can be considered a threshold for dermal uptake (ECB, 2003).

Based on the above, the dermal absorption factor is considered 10%.

 

Distribution / Accumulation

No information on the distribution of T003421 is available. Since the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. T003421 tends to concentrate in the adipose tissue and depending on the conditions of exposure may accumulate.

It is generally the case that substances with high log P values have long biological half-lives. On this basis, daily exposure to a substance with a log P value of around 4 or higher could result in a build-up of that substance within the body. Accumulation in the stratum corneum is possible to some extent. Highly lipophilic substances may persist in the stratum corneum but they will eventually be cleared as the stratum corneum is sloughed off. Based on the substance very low water solubility and high molecular weight, no accumulation is expected within the lungs or bones.

 

Metabolism

Once absorbed, T003421 is not expected to undergo phase I or II hepatic biotransformations as it is suspected to bypass the liver. No prediction can be made regarding the other biotransformations occurring via the cytochromes from other organs.

 

Excretion

Due to its moderate molecular weight, very low water solubility and non-ionized form of the molecule, T003421 and its metabolites will most likely be excreted through the faeces. Furthermore, T003421 may also be actively secreted through the bile.

 

 

References

EC 2003. Second edition of the Technical Guidance Document on risk assessment in support of Commission Directive 93/67/EEC for new notified substances and Commission Regulation (EC) No 1488/94 on risk assessment for existing substances (1996). Part I through IV. ISBN 92 -827 -8012 -0. Office for Official Publications of the European Communities, Luxembourg.

 

ECHA-17 -G-12 -EN - ECHA Guidance on information Requirements and Chemical Safety Assessment. Chapter R.11: PBT/vPvB assessment. Version 3.0. June 2017