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EC number: 438-940-2 | CAS number: -
- 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
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
No studies are available. The molecular structure, molecular weight, physico-chemical properties incl. water solubility and octanol-water partition coefficient of SPM-N do not favour a high oral absorption. The dermal absorption is considered to be very low. In case absorption occurs, the fraction absorbed will be metabolised and most likely be excreted via the urine. The unabsorbed fraction will mainly remain unmetabolised due to the polymerization of the substance and will be excreted via the faeces. SPM-N has a low bioaccumulation potential. The inhalation route is not relevant as the inhalation exposure can be considered negligible due to physico-chemical properties.
Key value for chemical safety assessment
Additional information
There were no studies available in which the toxicokinetic properties of 2-methyl-N-(4-sulfamoylphenyl) prop-2-enamide (SPM-N) were investigated. The toxicokinetic properties of the substance was assessed taking into account the available information on physico-chemical and toxicological characteristics, according to ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2012).
SPM-N is a monomer that binds chemically to other molecules to form a polymer. 3-6% of the monomer units remain unbound. At room temperature (20 °C) it is a non-dusting, free-flowing white powder that mainly aggregates into lumps with an MMAD of > 2000 µm (99.2% by weight) (Baker, 2007). The molecular weight is 240.28 and the log Pow 0.6 (Brekelmans, 2008), indicating that the substance is bioavailable via the oral route, according the ‘Lipinski rule of 5’ (Lipinski et al., 2001). According to the QSAR prediction SPARC, the dissociation constants (pKa) for all relevant reactions were lower than -2.42 or higher than 9.93 (Karickhoff, 2009). These reactions will occur with the S- and N-atoms in the molecule. Therefore, the molecule is expected to be present in a non-ionized form at the intestinal pH-levels. This form favours intestinal absorption. As the water solubility is low (30.3 mg/L at 20 °C), this may be a limiting factor of absorption.
Absorption
The observation of systemic toxicity following exposure by any route is an indication for substance absorption; this will not provide any quantitative information.
Oral:
In an acute oral toxicity study performed according to OECD 423, rats were administered 2000 mg/kg bw SPM-N by gavage (Stitzinger, 2008a). There was no mortality and no effects were observed up to and including the highest dose level, leading to an LD50 cut-off value of 5000 mg/kg bw, as defined in the guideline. No treatment-related effects were observed in a range-finding study, in which 3 rats/sex/group were administered up to 1000 mg/kg bw/day by gavage for 5 days (Van Otterdijk, 2008). In the main study, performed according to OECD 407, rats were dosed 50, 150 and 1000 mg/kg bw/day by gavage for 28 days (Van Otterdijk, 2008). No toxicologically relevant effects were noted at any dose level. There were no changes in liver weight or enzyme activity in the treatment group compared to the control group, which generally indicates an increased metabolic load caused by the administered substance. Generally, a lack of systemic effects both during the acute and subacute studies would indicate the substance has limited bioavailability.
To be absorbed, the substance has to cross biological membranes, either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility. In general, low molecular weight (MW ≤ 500) and moderate lipophilicity (log Pow values of -1 to +4) are favourable for membrane penetration and thus absorption. The molecular weight of SPM-N is relatively low with 240.28, and the log Pow is 0.6, which favours oral absorption of the compound. However, in general a substance needs to be dissolved before it can be taken up from the gastro-intestinal tract. Thus, due to its low water solubility, it is unlikely that the systemic exposure to SPM-N following oral exposure will be high.
Dermal:
The effect of dermal administration of SPM-N was assessed in an acute dermal toxicity study in rats (Stitzinger, 2008b). A dose level of 2000 mg/kg bw caused flat posture in 2/5 males and chromodacryorrhoea in 4/5 males and 1/5 females during the first 4 hours after administration. As these reactions may also be caused by stress, it is not clear if they are substance-related. No other treatment-related effects were noted. No systemic effects were observed after the topical application of up to 0.5 g in the irritation and sensitisation studies (Stitzinger, 2008c; 2008e). Sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Based on the low water solubility of SPM-N dermal absorption is anticipated to be low. Also its log P value and molecular weight does not favour dermal absorption (ECHA, 2012).
The QSAR tool EpiSuite was applied to calculate the dermal absorption, using the molecular weight, log Pow and water solubility values. A very low dermal absorption rate of 1.76 x 10-4 µg/cm2/h was predicted (US EPA, 2011). Taking into account the experimental toxicological characteristics, the physico-chemical properties and the calculated very low dermal absorption rate, the dermal absorption is considered to be very low.
Inhalation:
A substance may also be absorbed via the respiratory system. As the vapour pressure is < 1.33 x 10-8 Pa (at 20 °C), the inhalation exposure due to evaporation is very unlikely. The substance is a non-dusting powder with an inhalable fraction (MMAD < 100 µm) of < 0.8% (Baker, 2007). If particles are inhaled, they will be trapped on the mucous membrane in the trachea and bronchi, from where they will be transported by ciliary movement upwards to the throat and be swallowed or coughed out. Very few particles are expected to reach the lungs (bronchioles) at all. Based on these data, the bioavailibility of the substance via the inhalative route is considered to be negligible.
Distribution
In general, the smaller the molecule, the wider the distribution. Small, water soluble molecules and ions will diffuse through aqueous channels and pores. If the molecule is lipophilic (log Pow > 0), it is likely to distribute into cells (ECHA, 2012).
The log Pow value of 0.6 and the relatively small size of the molecule indicated that the substance can reach all tissues.
Substances with log Pow values of ≤ 3 are unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate during continuous exposures. SPM-N is poorly lipid soluble and thus unlikely to accumulate in adipose tissue during 8 h-workday scenarios.
Metabolism
The potential metabolites following enzymatic metabolism of the substance were predicted using the QSAR OECD toolbox 3.1 (OECD, 2013). This QSAR tool predicts which metabolites of the test substance may be created by enzymes in the rat liver and in the skin. For skin and liver each, two identical metabolites were predicted, namely the cleavage products after hydrolyses of the amide-bond.
There is no indication that SPM-N is activated to reactive metabolites under the relevant test conditions. No elevated toxicity was observed after oral treatment, nor was there evidence for differences in toxic potencies due to metabolic changes in in vitro genotoxicity tests. The studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) were negative, with and without metabolic activation (Verspeek-Rip, 2007; Lazová, 2013; Buskens, 2007).
The unabsorbed fraction will mainly remain unmetabolised due to the polymerization of the substance and will be excreted via the faeces.
Excretion
The fraction of the test substance that is not absorbed via the gastrointestinal tract will be excreted via the faeces. In the fraction that is absorbed, both the unmetabolised part and the metabolites have a molecular weight below 300 and will most likely be excreted via the urine.
Reference list
Baker, D. 2007. Particle size analysis on a sample of SPM-N. Report No. GLP/100900AR1V1/07. Chilworth Technology, Southampton, UK.
ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Nov 2012. Downloaded from:
http://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf
Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev.;46(1-3):3-26.
Karickhoff S.W. (Ed.) 2001. SPARC Online calculator, v4.6. University of Georgia, USA. Calculation performed 26 July 2012.http://archemcalc.com/sparc/
OECD (2013). (Q)SAR Toolbox 3.1. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 10 Oct 2013.http://toolbox.oasis-lmc.org/?section=overview
US EPA (2011). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.10. United States Environmental Protection Agency, Washington, DC, USA. Calculation performed 26 July 2012.
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