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Administrative data

Link to relevant study record(s)

Description of key information

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

Based on the moderate molecular weight (408,28 g/mol), a particle size of 227.24 µm (Mass Median Aerodynamic Diameter or MMAD), a very low water solubility (6.70 μg/L at 20 °C and pH 8.1-8.3), a high partition coefficient (log Kow of 7.5 at pH 5) and a low volatility (vapour pressure of <7.6E-9 kPa at 25°C), it can be expected that oral, dermal and respiratory absorption rates are low. The adverse effects of the 28-day oral repeated dose gavage toxicity study confirm the low oral absorption rate.

Once absorbed, T003063 is not expected to undergo phase I or II hepatic biotransformations as it is suspected to bypass the liver. Given the moderate molecular weight, poor water solubility and non-ionized form of the molecule, T003063 and its metabolites will most likely be excreted through the faeces. Furthermore, T003063 may also be actively secreted through the bile.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
10

Additional information

T003063 (CAS 898566-17-1) is a white powder with a moderate molecular weight (408,28 g/mol), a particle size of 227.24 µm (Mass Median Aerodynamic Diameter or MMAD), a very low water solubility (6.70 μg/L at 20 °C and pH 8.1-8.3), a high partition coefficient (log Pow of 7.5 at pH 7) and a low volatility (vapour pressure of 7.6 E-9 kPa at 25°C).

The backbone of T003063 is a thiophene with the following substituents: a phenyl group with a fluorine (ortho position) and a methylbenzyl group with an iodine (ortho position).

T003063 does not contain acidic or basic groups and is therefore in its non-ionized form at pH 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 T003063.

Absorption

Oral/GI absorption:

Absorption of T003063 is not considered to be likely to occur given its molecular weight < 500 g/mol, its log Pow value above 6 and its very low water solubility. These parameters taken together suggest that the absorption of a highly lipophilic substance like T003063 may be limited by their inability to dissolve into GI fluids and hence come in contact with the mucosal surface. However, its absorption will be enhanced if it undergoes micellular solubilisation by bile salts. T003063 is then likely to enter the circulation via the lymphatic system, bypassing the liver.

In an acute oral toxicity study (OECD guideline 423; Giannino, 2008), T003063 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. No adverse effects were demonstrated over a period of 14 days 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 guideline 422; Peter, 2016), T003063 was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg body weight/day. No parental toxicity, no reproduction or developmental toxicity were observed up to the highest dose level tested (1000 mg/kg/day).

There is thus no indication of significant uptake of the test item following oral administration.

 

Additionally, Kelly et al (2004) reported the relationship between dietary absorption efficiencies and log Kow for fish and mammals including humans (Kelly et al, 2004; O’Connor et al, 2013). All the dietary absorption efficiencies of highly hydrophobic chemicals showed tendencies to decrease with increasing log Kow values; chemicals with log KOW > 6 to 7 showed decrease in uptake efficiency to organisms. The authors considered this to be due to the restricted permeability of the highly hydrophobic chemicals into the unstirred water layer of the gastrointestinal tract. This phenomenon could be also attributable to the increased sorption of the chemicals to the indigestible fraction in the gastrointestinal tract. The log Kow >7 of the substance is a reasonable starting point for a limited oral absorption.

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

 

 

Respiratory absorption:

Because T003063 has a low volatility, the availability of the powder for inhalation as a vapour is limited. As its MMAD is larger than 100 µm, the majority of the solid particles will not be inhaled. Based on the above, the absorption of T003063 through inhalation is expected to be very low. 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 200 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.

Therefore, therespiratory absorption factor is estimated to be 10%.

 

 

Dermal absorption:

Since T003063 is a solid, the product will not readily be 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.

The highly lipophilic character of T003063 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 (6.70 μg/L) and its Log Kow above 6, the rate of transfer of T000363 between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake of T003063 into the stratum corneum itself may be slow.

 

An acute dermal toxicity study (OECD guideline 402; Latour, 2016) where 2000 mg/kg of T003063 was applied to 5 male and 5 female Wistar rats, demonstrated no effects related to the test material confirming the expectations described above. Furthermore, the substance is not irritating to skin based on anin vivoacute dermal irritation study (OECD guideline 404; Rached, 2015).

In a Local Lymph Node Assay (OECD guideline 429; Honarvar, 2008), the test item was found to be a skin sensitiser under the conditions of the test. However, no signs of adverse effects on mortality, body weight or clinical signs were noted. This fact suggests that the dermal absorption of T003063 is rather limited.

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

As a result, thedermal absorption factor is set to 10%.

 

Distribution/Accumulation

No information on the distribution of T003063 is available.

Supporting information from the ecotoxicological assessment of this substance was used to conclude on the absence of bioconcentration of the substance. Substances with log Kow between 4.5 and 6 are considered likely to be highly accumulating; however, no substantial bioconcentration is assumed for compounds having log Kow with values less than 4.5 or greater than 6. For substances with log Kow greater than 6, a gradual decrease of the BCF is observed and it has been hypothesized within the published literature that a high log Kow is more an effect of solubility than a tendency of the substance to be lipophilic (ECHA information requirements PBT assessment).

In terms of toxicokinetics, the above suggests that the substance (with log Kow >7) is not likely to accumulate in humans.

 

Metabolism

Once absorbed, T003063 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

Given the moderate molecular weight, poor water solubility and non-ionized form of the molecule, T003063 and its metabolites will most likely be excreted through the faeces. Furthermore, T003063 may also be actively secreted through the bile.

Although T003063 may persist in the stratum corneum after dermal exposure, it does not have the potential to penetrate the epidermis and will eventually be cleared as the stratum corneum is sloughed off.

 

 

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

Kelly BC, Gobas FAPC, McLachlan MS. 2004. Intestinal absorption and biomagnification of organic contaminants in fish, wildlife, and humans. Environ Toxicol Chem 23(10):2324-2336.


O’Connor IA, Huijbregts MAJ, Ragas AMJ, Hendriks AJ. 2013. Predicting the oral uptake efficiency of chemicals in mammals: Combining the hydrophilic and lipophilic range. Toxicol App Pharmacol 266:150-156.