Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 812-958-4 | CAS number: 1078712-76-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics, other
- Type of information:
- (Q)SAR
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Data source
Materials and methods
Test material
- Reference substance name:
- Reference substance 001
- Cas Number:
- 1078712-76-1
- Molecular formula:
- C23-27H49-59N (Substance is a UVCB)
- Test material form:
- liquid
Constituent 1
Results and discussion
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- minimal and slow absorption
- Type:
- distribution
- Results:
- Based on lipophilicity, absorbed material is likely to be distributed to fatty tissues
- Type:
- metabolism
- Results:
- Expected to be metabolized heavily by the liver to secondary alkyl amines followed by oxidation and phase II conjugation
- Type:
- excretion
- Results:
- Expected to occur primarily in the bile
Applicant's summary and conclusion
- Executive summary:
Summary
The notified substance does not have toxicokinetic (TK) data. Therefore, the TK assessment is based on the physical/chemical properties, information from standard toxicology studies (e.g., OECD 408 repeat dose study), QSAR modeling, and computational toxicology tools. Table 1 is an overview of key chemical information used in the assessment.
Table 1. Overview of chemical structure and physical/chemical properties.
Representative chemical structure
SMILES (used for QSAR and modelling)
CN(CCCCCCCCCCCCCC)CC(CC)CCCC
(smallest alkyl derivative)
Molecular weight (MW)
339.7-395.8
Water solubility
0.00048 – 0.00062 mg/L
Kow
6.1
Vapor pressure
3.275 X 10-5 Pa at 20°C
Physical state
Liquid
Estimates are for C14 because tallow is a C14-C18 range
The notified substance has the following TK characteristics:
I. Absorption
a. Oral: minimal and slow absorption
b. Dermal: minimal and slow absorption
c. Inhalation: not expected due to low vapor pressure
II. Distribution: Based on liphophilicity, absorbed material is likely to be distributed to fatty tissues
III. Metabolism: Expected to be metabolized heavily by the liver to secondary alkyl amines followed by oxidation and phase II conjugation
IV. Excretion: Expected to occur primarily in the bile
I. Absorption
a. Oral Absorption
The notified substance is expected to be absorbed after oral administration based on repeat dose toxcity studies but this is likely minimal and occurs slowly. The following information supports this:
1. Test data with the notified substance
The notified substance was bioavailable based on the effects observed in OECD 422 and OECD 408 oral gavage studies. This includes increased liver weight with associated enzyme changes that was concluded by the study director to be an adaptive response, most likely due to the metabolism that is expected to occur with the notified substance (see metabolism section).
2. Modeling using SwissADME (http://www.swissadme.ch/index.php)
Gastrointestinal absorption was predicted using SwissADME, which is a freely available web-based tool (Daina et al., 2017). SwissADME predicts the absorption and bioavailability based on a number of paramaters known to influence these properties, including physical/chemical properties, lipophilicity, and polarity.
The notified substance was assessed to have "low" GI absorption by SwissADME. In addition, the probability of the substances being a substrate or non-substrate of the permeability glycoprotein (P-gp) was calculated. P-gp plays a primary role among ATP-binding cassette transporters or ABC transporters in the active efflux through biological membranes. The notified substance was predicted to not be a substrate of P-gp, indicating it is unlikely to be involved in active transport processes.
3. Evaluation of critical physical/chemical properties known to influence absorption
Absorption of a chemical from the gastrointestinal (GI) tract depends on its physical properties, including lipid solubility and its dissolution rate. The European Chemicals Agency (ECHA) has established guidance for determining oral absorption potential (Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C: Endpoint Specific Guidance, November, 2014). As seen in Table 1, the molecular weight of the notified substance indicates that oral absorption may occur. However, based on the low water solubility and high Kow, absorption is likely limited.
Table 1. Physiochemical Properties and Oral Absorption
Physical and Chemical Parameter
Relationship to Absorption
Notified Substance
Molecular Weight
< 500: favorable for absorption
> 1000: do not favor absorption
339.7-395.8: indicates oral absorption may occur
Water solubility
Water soluble substances will dissolve in GI fluids and may be absorbed by bulk diffusion
Low water solubility indicates oral absorption is low
Kow
Values between -1 and 4 are favorable for passive diffusion
Kow of 6.1 indicates passive diffusion is low
b. Dermal Absorption
Dermal absorption of the notified substance is expected to be minimal based on the physiochemical properties and occur slowly based on the modeled Kp. Table 2 compares the physiochemical properties of the notified substance with the ECHA guidance for determining dermal absorption potential(Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C: Endpoint Specific Guidance, November, 2014). The molecular weight of the notified substance indicates that dermal absorption may occur; however, the material is very insoluble in water and the Kow exceeds the optimal cut-off criteria indicating that dermal absorption may occur but to a small extent.
Table 2. Physiochemical Properties and Dermal Absorption
Physical and Chemical Parameter
Relationship to Absorption
Notified Substance
Molecular Weight
< 100: favorable for absorption
> 500: too large for penetration
339.7-395.8: indicates dermal absorption may occur
Water solubility
< 1 mg/L: dermal uptake is likely to be low
0.00048 – 0.00062 mg/L indicates dermal absorption is low
Kow
Values between 1 and 4 are favorable for dermal absorption; > 6 very limited penetration and uptake
Kow of 6.1 indicates limited dermal absorption
The permeability coefficient (Kp) was estimated use EPA Dermwin v2.02 and SwissADME:
1. Dermwin v2.02 using measured Kow: 0.22 cm/hr
2. Dermwin v2.02 using EPISUITE predicted Kow: 62.1 cm/hr
3. SwissADME: 216 cm/hr (based on a prediction of log Kp of -1.23 cm/s)
c. Absorption via Inhalation
Inhalation is not considered a relevant route due to the low vapor pressure of 3.275 X 10-5 Pa at 20°C.
II. Distribution
If absorption occurs, the substance will likely be distribtuted somewhat to faty tissue based on its lipophilicity. However, wide distribution and accumulation are not expected due to the expected metabolism and excretion that will occur in the liver. This is also supported by the repeat dose data, specifically the adaptive changes in the liver where the material is likely undergoing metabolism.
III. Metabolism
It has been established that alkyl amines undergo extensive metabolism, including n-dealkylation (Casarett and Doulls, 2008). The metabolism of the notified substances was evaluated using LMC OASIS TIMES (v2.27.17.6) in vitroRat Liver S9 Simulator. The complete metabolism simulation report, with full details on the predicted metabolism, is attached.
The primary metabolic pathway predicted for tertiary amines is n-dealkylation, which is catalyzed by CYP 2D6 (de Groot et al., 1999), resulting in a secondary alkyl amine and an aldehyde. This is expected to occur completely and with high probability based on the TIMES model and is supported by the literature (Hanson et. al., 2010; Macherey and Dansette, 2008). The shortest alkyl chain is preferentially dealkylated to form the corresponding alkyl aldehyde.
The secondary alkyl amine subsequently undergoes oxidation (aliphatic c-oxidation) forming carbonyl or aldehyde groups that are further reduced (aldehyde dehydrogenase). This is supported by the metabolism summary in the SIAP for secondary alkyl amines (OECD, 2013), which states that they are oxidized to aldehydes. Ultimately, this is expected to lead to phase II conjugation (e.g., glucuronidation).
Aliphatic oxidation is consistent with what occurs for primary alkyl amines of similar chain length (EU, 2008), which further supports this metabolism assessment.
IV. Excretion
Based on the metabolic profile, some of the notified substance is expected to be conjugated to phase II enzymes and excreted in the bile due to large molecular weight. This is consistent with information on primary alkyl amines with a similar alkyl chain length, which have minimal urinary excretion (EU, 2008).
References
- deGroot M., M. Ackland, V. Horne, A.Alex, B. Jones, A Novel Approach to Predicting P450 Mediated Drug Metabolism. CYP2D6 Catalyzed N-Dealkylation Reactions and Qualitative Metabolite Prediction Using a Combined Protein and Pharmacophore Model for CYP2D6. J. Med. Chem. 1999
- Hanson, K.L., BandenBrink, B.M., Babu, K.N., Allen, K.E., Nelson, W.L., and Kunze, K.L. Sequential Metabolism of Secondary Alkyl Amines to Metabolic-Intermediate Complexes: Opposing Roles for the Secondary Hydroxylamine and Primary Amine Metabolites of Desipramine, (S)-Fluoxetine, and N-Desmethyldiltiazem. Drug Metabolism and Description. March 3, 2010
- Klassen, C. Casarett & Doull’s Toxicology. Seventh Edition. 2008
- Macherey, A.C and Dansette, P. Biotransformations Leading to Toxic Metabolites: Chemical Aspect. Chapter 33. Wermuth’s The Practice of Medicinal Chemistry. 2008
- OECD SIDS Initial Assessment Profile (SIAP). Aliphatic Secondary Amines. CoCAM4. April, 2013
- European Union Risk Assessment Report (EU RAR) – Primary Alkyl Amines. October, 2008
- Daina, A., Michielin, O., Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medical chemistry friendliness of small molecules. Scientific Reports. March 3, 2017
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.