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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
Toxicokinetic assessment of the substance based on the available data
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: since this is a theoretical assessment, the Klimisch value cannot be 1.
Objective of study:
other: oxicokinetic assessment of the substance based on the available data
Qualifier:
according to guideline
Guideline:
other: Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency
Version / remarks:
Version 3.0 (June 2017)
Deviations:
not applicable
GLP compliance:
no

TOXICOKINETIC ASSESSMENT

A chemical can enter the body via the gastrointestinal tract, the lungs and the skin. In general, a substance needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration.1 SHR 1396 consists of three constituents each with a molecular weight of 190.32 g/mol. The low molecular weight of the substance does favour absorption however due to the low water solubility of 0.0385 mg/L the substance will not dissolve readily in the GI fluids and thus passive uptake in the gastro-intestinal (GI) tract will be limited. The partition coefficient (log Pow) of the substance is experimentally determined to be between 7.0 and 7.2. The high log Pow indicates that the substance is lipophilic and can therefore be expected to form micelles when assisted by bile salts and as such be solubilized and absorbed from the GI tract into the lymphatic system or epithelial cells. As signs of systemic toxicity were observed in the oral toxicity studies absorption of the substance can take place from the GI tract. Based on the considerations mentioned above, for risk assessment purposes, oral absorption of the substance is set at 50%.

The substance has a low vapor pressure of 9.5 Pa and is therefore unlikely to reach the respiratory tract via inhalation as a vapor. The substance is a clear colourless liquid which can form fine droplets (aerosols) that can enter the nasopharyncheal region and subsequently the trachea/bronchial/pulmonary regions of lungs. In case the substance would reach these different regions, it will not readily diffuse or dissolve into the mucus lining the respiratory tract due to its very low water solubility and thus limit absorption. However lipophilic substances can be absorbed by micellular solubilization, in particular for substances that are highly lipophilic and have a low water solubility such as SHR 1396. Since signs of systemic toxicity are present in the oral toxicity study it is likely the substance can too be absorbed by lung tissue however as the substance is not directly available for uptake in the respiratory tract due to the low water solubility part of the undissolved substance may be cleared from the respiratory by mucocilliary mechanisms which transport it towards the pharynx where it is swallowed. Based on the above the inhalation absorption of the substance is set at 50% for risk assessment purposes.

According to the criteria given in the REACH Guidance, a default value of 100% dermal absorption should be used unless MW >500 and log Pow <-1 or >4, in which case a value of 10% skin absorption should be chosen2. The substance has a molecular weight below 500 and a log Pow of 7.0 – 7.2 indicating that a default value of 100% absorption must be considered. However the low water solubility combined with the high Log Pow will significantly slow down the rate of transfer between the stratum corneum and the epidermis resulting in limited absorption across the skin. Therefore, for risk assessment purposes, the dermal absorption of substance is set at 10%.

Once absorbed, wide distribution of the substance throughout the body is not expected due to the low water solubility of the substance however, as the substance is lipophilic, it is likely to distribute into cells. After oral absorption the substance may be metabolized in the gastrointestinal tract by the GI flora or in the liver after uptake. Lipophilic substances such as SHR 1396 tend to accumulate in adipose tissue under normal repeated intermittent exposure2, therefore the bioaccumulation potential is considered high. The major routes of excretion for substances from systemic circulation are the urine and/or the feces2. Due to its low water solubility and lipophilic character the substance can be excreted in the bile and subsequent the feces if no enterohepatic recycling occurs.

Conclusion:

A toxicokinetic assessment was performed based on the available data of the substance. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 50% (oral), 50% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is considered high.

Ref. 1 - Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

Ref. 2 - Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 3.0 June 2017.

Conclusions:
For risk assessment purposes, 50% is used for oral and inhalation absorption. 10% is used for dermal absorption
The bioaccumulation potential is expected to be high.

Description of key information

For risk assessment purposes, 50% is used for oral and inhalation absorption; 10% is used for dermal absorption.

The bioaccumulation potential is expected to be high.

Key value for chemical safety assessment

Bioaccumulation potential:
high bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
50

Additional information

TOXICOKINETIC ASSESSMENT

A chemical can enter the body via the gastrointestinal tract, the lungs and the skin. In general, a substance needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration.1 SHR 1396 consists of three constituents each with a molecular weight of 190.32 g/mol. The low molecular weight of the substance does favour absorption however due to the low water solubility of 0.0385 mg/L the substance will not dissolve readily in the GI fluids and thus passive uptake in the gastro-intestinal (GI) tract will be limited. The partition coefficient (log Pow) of the substance is experimentally determined to be between 7.0 and 7.2. The high log Pow indicates that the substance is lipophilic and can therefore be expected to form micelles when assisted by bile salts and as such be solubilized and absorbed from the GI tract into the lymphatic system or epithelial cells. As signs of systemic toxicity were observed in the oral toxicity studies absorption of the substance can take place from the GI tract. Based on the considerations mentioned above, for risk assessment purposes, oral absorption of the substance is set at 50%.

The substance has a low vapor pressure of 9.5 Pa and is therefore unlikely to reach the respiratory tract via inhalation as a vapor. The substance is a clear colourless liquid which can form fine droplets (aerosols) that can enter the nasopharyncheal region and subsequently the trachea/bronchial/pulmonary regions of lungs. In case the substance would reach these different regions, it will not readily diffuse or dissolve into the mucus lining the respiratory tract due to its very low water solubility and thus limit absorption. However lipophilic substances can be absorbed by micellular solubilization, in particular for substances that are highly lipophilic and have a low water solubility such as SHR 1396. Since signs of systemic toxicity are present in the oral toxicity study it is likely the substance can too be absorbed by lung tissue however as the substance is not directly available for uptake in the respiratory tract due to the low water solubility part of the undissolved substance may be cleared from the respiratory by mucocilliary mechanisms which transport it towards the pharynx where it is swallowed. Based on the above the inhalation absorption of the substance is set at 50% for risk assessment purposes.

According to the criteria given in the REACH Guidance, a default value of 100% dermal absorption should be used unless MW >500 and log Pow <-1 or >4, in which case a value of 10% skin absorption should be chosen2. The substance has a molecular weight below 500 and a log Pow of 7.0 – 7.2 indicating that a default value of 100% absorption must be considered. However the low water solubility combined with the high Log Pow will significantly slow down the rate of transfer between the stratum corneum and the epidermis resulting in limited absorption across the skin. Therefore, for risk assessment purposes, the dermal absorption of substance is set at 10%.

Once absorbed, wide distribution of the substance throughout the body is not expected due to the low water solubility of the substance however, as the substance is lipophilic, it is likely to distribute into cells. After oral absorption the substance may be metabolized in the gastrointestinal tract by the GI flora or in the liver after uptake. Lipophilic substances such as SHR 1396 tend to accumulate in adipose tissue under normal repeated intermittent exposure2, therefore the bioaccumulation potential is considered high. The major routes of excretion for substances from systemic circulation are the urine and/or the feces2. Due to its low water solubility and lipophilic character the substance can be excreted in the bile and subsequent the feces if no enterohepatic recycling occurs.

Conclusion:

A toxicokinetic assessment was performed based on the available data of the substance. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 50% (oral), 50% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is considered high.

Ref. 1 - Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

Ref. 2 - Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 3.0 June 2017.