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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
theoretical assessment
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.
GLP compliance:
no
Type:
absorption
Results:
For risk assessment purposes, 50% is used for oral and dermal absorption and 10% for inhalation absorption
Conclusions:
A toxicokinetic assessment was performed based on the available data of the substance. Based on the properties of the substance, absorption factors for this substance are derived to be 50% (oral), 10% (inhalation) and 50% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be high.

Description of key information

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), 10% (inhalation) and 50% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be high.

Key value for chemical safety assessment

Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
10

Additional information

After exposure, a substance can enter the body via the gastrointestinal tract, the lungs, and the skin. Since different parameters are relevant for absorption via the different routes of exposure, the uptake via these three routes will be addressed individually. After oral administration, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract. The water solubility of 4,4'-methylenebis-N-sec-butylaniline is very low (0.0015 g/L at 20°C) , therefore the substance is expected to dissolve into the gastrointestinal fluids only to a limited extent. Consequently, the substance is expected to be poorly available for uptake. Based on its molecular weight (310.48), uptake via passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage across membranes with the bulk passage of water) can occur, but this will be limited due to its poor water solubility. On the other hand, micellular solubilization may occur related to its lipophilicity (log Pow = 5.4). Substances absorbed as micelles can enter the circulation via the lymphatic system. The calculated dissociation constant (pKa) of the test substance is 4.89 and 5.98, which means that at pH values usually found in the gastrointestinal tract (roughly between 2 and 8), the substance could be ionized. Ionization of the substance can hamper uptake. The oral toxicity data indicates that there is absorption to some extent. In conclusion, for risk assessment purposes oral absorption of 4,4'-Methylenebis-N-sec-butylaniline is set at 50%, taking into account its low water solubility and expected ionized state in the gastro-intestinal tract which will both limit absorption, but also considering potential uptake via passive diffusion and its potential to be taken up via micellular solubilization.  4,4'-Methylenebis-N-sec-butylaniline has been found to have a low vapor pressure (2.1 × 10 -6 at 25°C), which indicates that its availability for inhalation as a vapor is low, and the exposure via air will be limited. On the other hand, 4,4'-Methylenebis-N-sec-butylanilineis a liquid at room temperature, which implies that exposure via aerosols is possible. Aerosols can reach the tracheobronchial region, in which case 4,4'-Methylenebis-N-sec-butylaniline may dissolve in the mucus lining the respiratory tract to a limited extent. Although some absorption may occur, its low water solubility is expected to hamper direct absorption. Therefore the substance is considered to enter the body only to a limited extent and the largest part will leave the lungs e.g. through coughing. However, this substance may be taken up by micellular solubilization. This mechanism could be of particular importance because this substance is highly lipophilic (log Pow > 4) and poorly soluble in water (water solubility < 1 mg/L). The substance is not surface active and has no irritant properties, therefore no damage of the epithelia is expected that could enhance uptake. Taking these considerations together it is concluded that for risk assessment purposes, the inhalation absorption of 4,4'-Methylenebis-N-sec-butylaniline is set at 10%. 

As 4,4'-methylenebis-N-sec-butylaniline is a liquid, uptake through the skin can occur. The high partition coefficient (log Pow: 5.4) allows uptake in the stratus corneum, but its low water solubility (0.0015 g/L at 20°C) will limit the partitioning from the stratum corneum into the epidermis. According to the criteria given in the REACH Guidance, 10% dermal absorption will be considered in case MW >500 and log Pow <-1 or >4, otherwise 100% dermal absorption should be used. Thus according to the guideline, 4,4'-Methylenebis-N-sec-butylaniline uptake should be set at 100%. However, it is in general assumed that dermal absorption does not exceed oral absorption. Moreover, as discussed above, the substance is not surface active and has no irritant properties, thus no damage on the epithelia is expected that could enhance the uptake. Therefore, for risk assessment purposes, dermal absorption is set at 50%. 

Once absorbed, distribution of the substance throughout the body is expected due to its moderate molecular weight. However, its limited water solubility and high partition coefficient will limit distribution. 4,4'-Methylenebis-N-sec-butylaniline may be metabolized in the gastrointestinal tract or the liver and be excreted through bile. Based on its high coefficient (log Pow = 5.4), 4,4'-Methylenebis-N-sec-butylaniline might accumulate in adipose tissue (intracellular concentration may be higher than the extracellular concentration). In general, substances with a high partition coefficient (> 4) have long biological half-lives. If the metabolism is not efficient enough, this substance could accumulate in the body upon continuous exposure, therefore the bioaccumulation potential of 4,4'-Methylenebis-N-sec-butylaniline is expected to be high.

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