Reaction mass of bis[4-(vinyloxy)butyl] hexane-1,6-diylbiscarbamate and 9,18-dioxo-3,8,19-trioxa-10,17-diazapentacos-1-en-25-yl [6-({[4-(vinyloxy)butoxy]carbonyl}amino)hexyl]carbamate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2016

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, 10% is used for oral and dermal absorption. For inhalation absorption 100% should be used.

Conclusions:

For risk assessment purposes, 10% is used for oral and dermal absorption. For inhalation absorption 100% should be used. Distribution and bioaccumulation of P 1920C is expected to be limited.

Executive summary:

Based on a theoretical assessment of all available data, P 1920C is expected to absorb to a limited extent by the oral and dermal route. A value of 10% is proposed for both routes for risk assessment. Exposure via the respiratory route is expected for a minor part of the particulates. A value of 100% is proposed as worst case for the respiratory route for risk assessment.

Distribution and bioaccumulation of P 1920C is expected to be limited. Cytochrome P450 metabolism is predicted to consist mainly of O-dealkylation or epoxidation of the vinylether, and N-dealkylation, which are expected to be converted to less toxic substances rapidly as all genotoxicity tests performed were negative.

Description of key information

Based on a theoretical assessment of all available data, P 1920C is expected to absorb to a limited extent by the oral and dermal route. A value of 10% is proposed for both routes for risk assessment. Exposure via the respiratory route is expected for a minor part of the particulates. A value of 100% is proposed as worst case for the respiratory route for risk assessment.

Distribution and bioaccumulation of P 1920C is expected to be limited. Cytochrome P450 metabolism is predicted to consist mainly of O-dealkylation or epoxidation of the vinylether, and N-dealkylation, which are expected to be converted to less toxic substances rapidly as all genotoxicity tests performed were negative.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

A substance can enter the body via the gastrointestinal tract, the lungs, and the skin. To determine the absorption rate, the different routes are assessed individually. It is of note that although the vinylether group present in various components of this multi-constituent compound is expected to release acetaldehyde in contact with water, the assessment is done on the multiconstituent compound as a whole. This is prompted by the fact that the physico-chemical properties and the toxicological data available are based on the properties of the entiremulticonstituent compound, the substance to be notified.

 

Generally, a compound needs to be dissolved before it can be taken up from the gastrointestinaltract after oral administration. P 1920C has a very low water solubility (water solubility <8μg/Lat 20°C) and is thus expected to dissolve only to a minor extent in the gastrointestinal fluids. The absorption via passive uptake is thus expected to be limited. The different constituents have a moderate to high molecular weight (approximately 400 Da to 686 Da for the two main constituents), which will limit passage through biological membranes. Small amounts of such substances may be transported into epithelial cells by pinocytosis or persorption (passage through gaps in membranes left when the tips of villi are sloughed off). Based on the partition coefficient of 3.4 (log Pow related to 78.8% of the substance) or higher (4.6 and 6.3 for 13.9% and 7.3% of the substance, respectively), uptake via micellular solubilisation can be expected to take place. In conclusion, the moderate to relatively high molecular weight (400 to 686 Da), moderate to high log P (3.4 or higher) and low water solubility (<0.9 mg/L) are indicative for limited absorption. Therefore, for risk assessment purposes oral absorption of P 1920C is set at 10%. The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

The low vapour pressure (1.2 × 10-7 Pa at 25°C) and the absence of a boiling point (reaction and/or decomposition of the test substance starts at 250°C) indicate that P 1920C is a substance with low volatility. Therefore it is not likely that P 1920C will reach the nasopharyncheal region or subsequently the tracheo/bronchial/pulmonary region via inhalation of vapour. The main fraction of the particles are > 250 μm (approximately 98.9%) and around 0.93% has a size between 250 and 63 μm. For the remaining 0.15%, the mean particle size was determined to be approximately 31 μm, with 50% of this fraction below 28 μm and 10% smaller than 4 μm. In humans, only particles with aerodynamic diameters below100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm thealveolar region of the respiratory tract. Based on the size of the particles, only a small fraction of P 1920C is therefore expected to be able to reach all parts of the lung upon inhalation. However, due to its very low water solubility, P 1920C is expected to be retained within the mucus, where it may be removed by macrophages or be absorbed across the respiratory tract epithelium by passive diffusion based on the moderate logPow of the main part of its constituents. The constituents with higher Pow will be taken up preferentially via micellular solubilisation as a result of dissolution in the mucus lining the respiratory tract. Based on these considerations, for risk assessment purposes the inhalation absorption of P 1920C is set at 100% as a worst case. P 1920C is a lumpy powder and as its water solubility is very low, it will only dissolve to a very small extent into the surface moisture of the skin to allow uptake. The relatively large size of the components (approximately 400 Da to 686 Da for the main constituents), is expected to hamper uptake as well. Therefore, penetrance of the first skin layer, the stratum corneum (non-viable layer of corneocytes forming a complex lipid membrane), is expected to be limited. On the other hand, based on its lipohilicity, it can be predicted that the substance will be able to cross the viable epidermis. Since the log Pow of the substance is 3.4 to 6.3 and the molecular weight of the main component is approximately 400 Da, the substance specific data do not meet thecriteria for 10% dermal absorption as given in Endpoint Specific Guidance (MW> 500 and log Pow <-1 or >4). However, as it is generally accepted that dermal absorption does not exceed oral absorption, 10% dermal absorption of P 1920 C is considered a realistic dermal absorption factor for risk assessment purposes. Therefore, a 10% dermal absorption factor for P 1920C is considered to be appropriate. The results of the dermal studies do not provide reasons to deviate from this proposed dermal absorption factor.

Once absorbed, distribution of the test substance throughout the body is expected to be limited based on its high molecular weight. Based on the lipophilicity of the different constituents (a partition coefficient of 3.4 or higher), P 1920C may accumulate to a limited extent in adipose tissue. However, taking into consideration its moderate to high molecular weight and the very low water solubility, the distribution and bioaccumulation potential of P 1920C is expected to be low. The toxicity studies performed do not provide reasons to conclude otherwise.

Prediction of possible cytochrome P450 metabolism by TOXTREE shows that P 1920C is likely to be metabolised via O-dealkylation or epoxidation of the vinylether, and N-dealkylation. The epoxides and aldehydes formed have not induced any effects in the genotoxicity tests and repeated dose studies performed. This may indicate that detoxifying mechanisms are in place, such as further oxidation or conjugation of metabolites formed.