D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-, 2,3,4,6-tetrakis(2,2-dimethylpropanoate), (1S)-

Endpoint summary

Description of key information

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

 

Based on the high molecular weight (781.0 g/mol), high partition coefficient (log Kow > 7.2 mg/L at pH 7), and low water solubility (<10 mg/l), it can be expected that oral absorption is unlikely. The acute oral toxicity study performed showed no adverse effects with LD50 established as greater than 2000 mg/kg body weight. In a combined repeated dose toxicity with the reproductive/developmental toxicity screening test, T003422 did not reveal any parental toxicity, reproduction and developmental toxicity for a treatment up to 1000 mg/kg. A 90-day study did not show any test item related changes in the investigated parameters and a prenatal developmental toxicity study showed no maternal and no developmental toxicity. Based on the low volatility and low water solubility, the absorption of T003422 through inhalation is expected to be low. The dermal absorption factor for T003422 is set to 10% based on the fact that the substance is a solid, its water solubility is low, and its molecular weight is high. Furthermore, T003422 is considered non-irritant and non sensitizing.

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

T003422 (CAS 1283129-18-9) is a white powder with a high molecular weight of 781.0 g/mol, a particle size of 22.131 µm (Mass Median Aerodynamic Diameter or MMAD), and a low water solubility of < 10 mg/L (at 21.5°C and pH 7.7). The partition coefficient was determined to be log Kow > 7.2 at pH 7 and the vapour pressure was assessed to be < 2.1E-8 Pa at 25°C.

 

The backbone of T003422 is 1,5-anhydro-D-glucitol with four 2,2-dimethylpropanoyl groups attached to the oxygen atoms of the hydroxy and hydroxymethyl substituents of the backbone. Furthermore the structure has a 3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl substituent at position 1. Since T003422 does not contain ionisable groups, no pKa could be calculated and no dissociation of the compound at neutral pH is expected.

 

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 T003422.

 

Absorption

Oral/GI absorption:

T003422 has a low water solubility which would lead to restricted dissolution of the substance into the gastrointestinal fluids and absorption through passive diffusion.

However, T003422 has a high partition coefficient (log Kow > 4). Any lipophilic compound can be taken up by micellular solubilization, especially highly lipophilic compounds that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed. It is generally assumed that the absorption along the gastrointestinal tract predominantly takes place in the small intestine since it has a very large surface area and the longest transit time.

 

No systemic toxicity was observed following a single dose up to 2000 mg/kg of T003422 in an acute oral gavage toxicity study with female mice (OECD 425, Herlich, 2012). LD50 was determined to be greater than 2000 mg/kg.

 

A combined 28-days repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422; Peter, 2017) has been performed by oral gavage with T003422 on Wistar (Han) rats (40 males and 40 females) applying following doses: 110, 330 and 1000 mg/kg/day (and a control group), for a duration of treatment of 29 days (males) or 50-56 days (females that delivered) or 39 days (females that failed to deliver). No toxicologically relevant changes in body weights and body weight gain were noted over the treatment period. Clinical biochemistry and haematological parameters were unaffected by treatment.

The results of the reproductive and developmental study show that, one out of the ten couples of the 110 mg/kg group experienced a total litter loss. A histopathology inflammation of the uterine endometrium was noted but this finding was attributed to the early post-natal phase at the time of total litter loss and was not considered test item-related. All other tissues (including mammary gland) were normal. Length and regularity of the estrous cycle were not affected by treatment. All females had regular cycles of 4-5 days. Spermatogenic staging profiles were normal (at least unilateral) for all males examined. Mating, fertility, gestation, post-implantation survival and lactation indexes were not affected by treatment.

Deficiencies in maternal care were observed for one female at 330 mg/kg (no. 61). Three pups were noted cold on PND 2 and two pups had a lean appearance on one or more days during PND 1-10. In addition, 2/10 pups were found missing on PND 2-4. The remaining pups survived until scheduled necropsy on PND 13. As this was observed for a single female of the mid dose group only, it was considered unrelated to treatment.

No treatment-related effects were noted in any of the developmental parameters investigated in this study (i.e. gestation, viability and lactation indices, duration of gestation, parturition, sex ratio, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight, anogenital distance (PND 1), areola/nipple retention (PND 13 males), T4 thyroid hormone levels (PND 13-15) and macroscopy.

In conclusion, treatment with T003422 by oral gavage in male and female Wistar Han rats at dose levels of 110, 330 and 1000 mg/kg revealed no parental, reproduction and developmental toxicity up to 1000 mg/kg and the No Observed Adverse Effect Level (NOAEL) was concluded to be of at least 1000 mg/kg.

 

In a 90-day study (OECD 408; Lourens, 2022), T003422 was administered daily via oral gavage to male and female Wistar Han rats at dose levels 110, 330 and 1000 mg/kg/day/day (10 rats/sex/group). There was no premature death in this study. No test item-related changes were noted in any of the of the parameters investigated in this study (i.e. mortality, clinical observations, functional observations, ophthalmoscopy, body weight, food consumption, clinical pathology investigations (i.e., hematology, coagulation and clinical chemistry parameters), and pathological examinations (i.e., organ weight changes, necropsy or microscopic findings)). Based on these results, the No Observed Adverse Effect Level (NOAEL) was considered to be a least 1000 mg/kg/day.

 

In a prenatal development toxicity study (OECD 414; Bressers, 2021), 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, thyroid gland weights, uterine contents, microscopic examination of the thyroid gland, corpora lutea, implantation sites and pre- and post-implantation loss.

In addition, the following parameters were determined and evaluated for the F1-generation:

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 were observed in any of the dose group tested. The maternal and developmental No Observed Adverse Effect Levels (NOAELs) for JNJ-42808415-AAA (T003422) was at least 1000 mg/kg/day.

 

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

 

 

Respiratory absorption:

 

Given its low volatility (vapour pressure < 0.5 kPa), the availability of T003422 for inhalation as a vapour is limited. However, since its MMAD is smaller than 50 µm, the solid particles have the potential to be inhaled and reach the thoracic region. Lipophilic substances have the potential to be absorbed directly across the respiratory tract epithelium. There is some evidence to suggest that substances have a longer half-life within the lungs, but this has not been extensively studied (Cuddihy and Yeh, 1988). Since T003422 has a high partition coefficient (log Kow > 4), it is favorable for absorption by micellular solubilisation especially because of its poor solubility in water. However, it is also due to its low water solubility that the rate at which the particles dissolve into the mucus will limit the amount that could be absorbed directly when reaching the respiratory system. Poorly water-soluble dusts, such as T003422, 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. Poorly water-soluble dusts depositing in the alveolar region would mainly be engulfed by alveolar macrophages which will either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues.

 

Based on the physicochemical properties (the low vapour pressure and very low solubility), the respiratory absorption factor is set to 50%.

 

Dermal absorption:

 

T003422 is a solid substance and therefore not readily taken up by the skin in comparison to liquid products. Moreover, its high molecular weight makes absorption even more unlikely. The product will have to dissolve into the surface moisture of the skin before uptake can take place. This is also not probable considering its low water solubility.

The dermal uptake is expected to be low since the substance is not soluble enough in water to partition from the stratum corneum into the epidermis.

It is expected that, given the penetration of T003422 into the lipid rich environment of the stratum corneum, absorption will be favoured due to the high lipophilic character of (log Kow >7.2) of the substance.

 

The acute dermal LD50 value of T003422 in Wistar rats (female and male) was established to exceed 2000 mg/kg body weight (OECD 402, Latour, 2016). Based on results, test substance does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity. Based on an in vitro skin irritation test (according to OECD guideline 439; Eurlings, 2016) T003422 was observed to be non-irritating to skin and is classified as a skin irritant according the criteria of the CLP regulation (EC) No 1272/2008. Based on a skin sensitization test (according to OECD guideline 429; Moor, 2012) results, the substance T003422 was not considered a skin sensitiser.

As a result, the dermal absorption factor for T003422 is set to 10%.

 

Distribution

The very water solubility will limit the distribution of T003422 through the body through aqueous channels and pores. T003422 also has a high molecular weight and in general, the larger the molecule, the lower the distribution. However, the substance is very lipophilic (log Kow of >7.2) and has the potential to distribute into the cells to a certain extend. Based on the toxicological studies, there were no test item-related alterations in organ weights. Based on these observations it can be concluded that T003422 will only distribute within the body to a limited extent. 

 

Accumulation

Based on its high Log Kow, T003422 tends to concentrate in the adipose tissue and depending on the conditions of exposure may accumulate. In general, substances with high log Kow values have long biological half-lives (Cuddihy and Yeh, 1988). Daily exposure to a substance with a log Kow value of around 4 or higher could result in a buildup 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 low water solubility and high molecular weight, no accumulation is expected within the lungs or bones.  

 

Metabolism

Based on its structure, T003422 might undergo phase I biotransformation reactions such as - 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 T003422 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.