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EC number: 447-010-5 | CAS number: 670241-72-2 ISONONYLBENZOAT
- 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
- Type of information:
- other: Expert judgement
- Adequacy of study:
- weight of evidence
- Rationale for reliability incl. deficiencies:
- other: Expert Judgement
Data source
Reference
- Reference Type:
- other:
- Title:
- Unnamed
- Year:
- 2 019
Materials and methods
Test material
- Reference substance name:
- isononyl benzoate
- Cas Number:
- 670241-72-2
- IUPAC Name:
- isononyl benzoate
Constituent 1
Results and discussion
Applicant's summary and conclusion
- Conclusions:
- No toxicokinetic studies are available. The toxicokinetics of INB was assessed based on physico-chemical data, the toxicological profile and literature data.
The molecular weight, water solubility, octanol/water partition coefficient and QSAR predictions favours oral absorption, whereas dermal and inhalative absorption is considered to be very low. High dose effects in repeated dose studies further demonstrate that systemic distribution takes place. With the log P value of 6.1 – 6.4, INB is highly lipophilic and thus will tend to concentrate in adipose tissue. After oral take up and intestinal absorption it is assumed that INB will be hydrolysed by cleavage of the ester bond and then further metabolized. The results of the repeated dose oral toxicity study in the rat do suggest that enhanced hepatic metabolism does take place. - Executive summary:
General
INB (also named Benzoic Acid Isononylester)is an ester ofbenzoic acid (BA) (EC No. 447-010-5, CAS No. 670241-72-2), also referred as Nonylbenzoate, branched and linear.
No experimental data on absorption, distribution, metabolism and excretion of INB are available.
According to REACH, the human health hazard assessment shall consider the toxicokinetic profile (Annex I). However, generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACH Annex VIII, 8.8.1).
Qualitative information on toxicokinetic behaviour can be derived taking into account the information on the chemical properties of the compound as well as data obtained in a basic data set. Furthermore, the behavior of the formed metabolites within the body should be taken in account.
Absorption
The observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information. Results from the oral repeated dose toxicity study in the rat shows evidence of systemic toxicity which indicates some degree of absorption of test material. Data from acute dermal and inhalation toxicity studies do not give any indication that enhanced absorption occur via the dermal or inhalation route of exposure.
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, and water solubility. In general, low molecular weight (MW ≤ 500) and moderate lipophilicity (log P values of - 1 to + 4) are favourable for membrane penetration and thus absorption. The molecular weight of INB is relatively moderate with 248 g/mol, favouring oral absorption of the compound; however, the substance is highly lipophilic (log of 6.1 – 6.4) and water solubility is very low (< 1 mg/L) indicating that absorption by passive diffusion may be limited. For highly lipophilic substances uptake by micellular solubilisation may be of particular importance, particularly for those that are poorly soluble in water (1 mg/L or less) (ECHA Guidance R.7c, Chapter R7.12.2.1).
Rarely, exogenous compounds may be taken up via a carrier mediated or active transport mechanism. However, prediction in this direction is not generally possible. Active transport (efflux) mechanisms also exist to remove exogenous substances from gastrointestinal epithelial cells thereby limiting entry into the systemic circulation. From physicochemical data, identification of substances ready for efflux is not possible.
Dermal uptake is expected to be moderate at this molecular weight level (< 100: dermal uptake high; > 500: no dermal uptake). However, for dermal uptake, sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Therefore, at the water solubility level of below 1 mg/L, dermal uptake is likely to be low. The log P of 6.1 – 6.4 supports this estimation; at values above 6 the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. As a conclusion, based on the high log P outside the range of - 1 to 4, a default value of 10% skin absorption can be used for risk assessment (ECHA Guidance R.7c, Chapter R7.12.2.1).
For respiratory uptake it can be considered that generally liquids would readily diffuse/dissolve into the mucus lining. Thereby, lipophilic substances with moderate log P values (between - 1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. However, any lipophilic compound may be taken up by micellular solubilisation. This mechanism may be of particular importance for highly lipophilic compounds (log P > 4) like INB, which are poorly soluble in water (1 mg/L or less) and that would otherwise be poorly absorbed (ECHA Guidance R.7c, Chapter R7.12.2.1). The low vapour pressure value of INB suggesting a low potential for inhalative exposure.
Thus, in the following QSAR predictions and reference to other well-studied substances were taken into account. QSAR predictions obtained from the Danish (Q)SAR database (2009) for one of the isomers (Di-n-pentyl-terephthalate) revealed the gastrointestinal absorption to be about 100% for a 1 mg dose, whereas dermal uptake is predicted to be very low (0.000146 mg/cm2/event).
It can be summarized that the moderate molecular weight of INB of 248 g/mol would allow direct absorption through membranes, however, passive diffusion is most probably very limited by the high lipophilicity and the low water solubility. It this therefore assumed that oral and respiratory uptake might roughly be in the same moderate range; whereas dermal absorption is considered to be very low.
Distribution
Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound.
The smaller a molecule, the wider is its distribution throughout the body. The molecular weight of 248 g/mol of INB indicates a moderate distribution in the body. Through its high lipophilie (log P = 6.1 – 6.4), INB is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissue.
The results of the toxicity studies identify no target organ toxicity. In addition, no effects on spermatogenesis were observed in the repeated dose toxicity study, thus no conclusion regarding blood-testes barrier penetration can be drawn. High dose effects further demonstrate that some systemic distribution takes place.
Bioaccumulation
Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, highly lipophilic (log P > 4) compounds tend to have longer biological half-lives. Thus, they potentially accumulate within the body in adipose tissue, especially after frequent exposure (e.g. at daily work) and the body burden can be maintained for long periods of time. After the stop of exposure, the substance will be gradually eliminated dependent on its half-life. During mobilization of fat reserves, e.g. under stress, during fasting or lactation, release of the substance into the serum or breast milk is likely, where suddenly high substance levels may be reached.
After dermal exposure, highly lipophilic (log P between 4 and 6) compounds may persist in the stratum corneum, as systemic absorbance is hindered.
With the log P value of 6.1 – 6.4, INB is highly lipophilic and thus will tend to concentrate in adipose tissue.
Metabolism
Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. It is even more difficult to predict the extent of metabolism along different pathways and species differences possibly existing.
Evidence for differences in toxic potencies due to metabolic changes can be derived for instance from in vitro genotoxicity tests conducted with or without metabolic activation. Regarding the in vitro genotoxicity of INB, all studies in mammalian cells regarding chromosome aberration (OECD 473) and micronucleus (OECD 474) incidence revealed a negative outcome with metabolic activation by S9-mix, which does not show a toxification effect.
After oral take up and intestinal absorption it is assumed that INB will be hydrolysed by cleavage of the ester bond and then further metabolized.
The results of the repeated dose oral toxicity study in the rat do suggest that enhanced hepatic metabolism does take place. Slightly elevated liver weights after high dose exposure are indicative of an increased liver metabolism.
Excretion
Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product.
Possible excretion ways of the metabolites of INB can be assumed of the repeated dose oral toxicity study in rats, which show that the kidney is a potential route of INB following hepatic metabolism.
Literature
Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance, European Chemicals Agency, ECHA-14-G-06-EN, November 2014.
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