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EC number: 249-047-0 | CAS number: 28473-19-0
- 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
Description of key information
Additional information
BACKGROUND
The three alkyl diesters dioctyl sebacate (DOS), di-(2-ethylhexyl) sebacate (DEHS) and diisodecyl adipate (DIDA) were assessed for suitability as read-across source substances for registration of diisodecyl sebacate (DIDS), as certain data for DIDS were not available to fulfil all the REACh data requirements stipulated in Annex VII-IX.
A data matrix (see below) was prepared to facilitate comparison of information on the key data points, as mandated in recent guidance from ECHA (2013). Where available, data were obtained from the primary literature, expert reviews and available study reports. In addition, some data were obtained from Structure Activity Relationship (SAR) and Quantitative SAR analyses generated using the OECD QSAR Toolbox (version 3.1, OECD, 2013).
THE READ-ACROSS APPROACH
Read-across involves the use of endpoint information for one chemical (the source chemical) to predict the same endpoint for another (untested) chemical (the target chemical). This can be a valid approach if the substances are considered to be sufficiently "similar". In principle, read-across can be used to predict physicochemical properties, toxicity, environmental fate and ecotoxicity. For any of these endpoints, it may be performed in a qualitative or quantitative manner (ECHA, 2008b; OECD, 2007). The degree of uncertainty associated with a read-across operation is minimised when the assessor has at their disposal a mechanistic understanding of the critical molecular structure/substructures related to the toxicological endpoint of interest. A read-across case can be particularly convincing when the source and target chemicals are shown to cause effects by a common mechanism or mode of action (MOA).
Structural similarity between chemicals is commonly used as a major basis for read-across, and the process is similar to a SAR assessment. Endpoint information is read-across from a structural analogue, a source chemical possessing physicochemical and toxicological properties that are likely to be similar to those of the target chemical as a result of a close structural relationship. A judgement on structural similarity may be based on the following:
a) a common functional group;
b) a common precursor and/or breakdown product, that results via physical or biological processes (metabolic pathway similarity).
c) the absence of novel functional groups of concern in the target chemical.
Analogues can also be chosen on the basis of common MOAs and similarities in chemical (or biochemical) reactivity. The main application of qualitative read-across is in hazard identification (ECHA, 2008b; OECD, 2007).
Read-across must, in all cases, be justified scientifically and documented thoroughly (ECHA, 2013). The supporting documentation is essential in allowing independent assessment of the adequacy of the read-across approach undertaken. It should include details of and justification for the read-across hypothesis, a list of all substances and endpoints included in the approach, a data matrix summarising the key data points (or their absence) and a conclusion on the suitability of the proposed approach.
READ-ACROSS TO DIDS
IDENTIFICATION AND STRUCTURAL SIMILARITIES
The target substance is diisodecyl sebacate (DIDS), an alkyl diester consisting of a central sebacic acid (decanedioic acid) moiety and two terminal isodecyl (8-methylnonyl) chains. The three chosen source compounds are also alkyl diesters, of similar molecular weight and chain length.
a) dioctyl sebacate (DOS), which consists of a central sebacic acid moiety and two terminal n-octyl chains;
b) di-(2-ethylhexyl) sebacate (DEHS), which consists of a central sebacic acid moiety and two terminal 2-ethylhexyl chains;
c) diisodecyl adipate (DIDA), which consists of a central adipic acid (hexanedioic acid) moiety and two terminal isodecyl chains.
The key structural elements (functional groups) of the target and source compounds are the same: all four contain two ester linkages within a long, saturated alkyl chain. The chemicals have a similar molar mass. It is expected that these would breakdown by hydrolysis to a dicarboxylic acid and two alcohols. The molar masses of the acid and alcohol produced from all four diesters are also similar.
ENVIRONMENTAL FACTORS
The target compound, DIDS, is readily biodegradable (79% degradation was reported after 28 days). Degradation of 65-78% was reported for all three source compounds. This suggests that all four compounds are unlikely to persist in the environment.
Bioconcentration Factors (BCFs) of <110 are predicted for DIDS, DEHS and DIDA. On the basis that BCF thresholds of 2000 and 5000 indicate a compound to be bioaccumulative and very bioaccumulative, respectively, no bioaccumulation of the target or source compounds is expected.
TOXICOKINETICS
No experimental toxicokinetic data were identified for the target or source compounds; this assessment of toxicokinetics, therefore, is based on physico-chemical properties and structural considerations.
The physico-chemical characteristics shared by all four compounds (high molecular weight, high log Pow and low water solubility), would tend to predict that absorption of intact diester after oral or dermal administration would be low. However, this fails to take into account the high probability of gastro-intestinal hydrolysis following oral exposure, and the likely extensive absorption of the hydrolysis products. The high boiling point and low vapour pressure indicates that none of these compounds are volatile at room temperature; as such no inhalation exposure is expected.
Their physico-chemical properties per se provide support for the possibility that the diesters potentially could accumulate in adipose tissue. In reality, absorption is likely to involve mainly the hydrolysis products (acid, alcohol) and these are expected to follow normal metabolic pathways for acids and alcohols e.g. oxidative metabolism and conjugation. Any absorbed DIDS will likely be hydrolysed e.g. by blood esterases to yield the acid and alcohol. Thus the chances of actual distribution to the tissues, and bioaccumulation of intact DIDS are low. Any non-utilised products may be excreted in the urine (e.g. soluble conjugates) or (if insoluble) in the faeces via the bile.
PHYSICO-CHEMICAL PROPERTIES
The molecular weights of all the compounds are > 400 g/mol and all are liquid at room temperature (melting points < -50 °C). DIDS, DIDA and DEHS are all practically insoluble in water. The boiling point of DIDS is about 420 °C at 1 atm; the boiling point of DIDA is similarly high (385 °C). Boiling points at reduced pressure are > 200 °C (DOS; DEHS). Vapour pressures are very low, in the order of 10-5 Pa (DIDA) or 10-6 Pa (DIDS; DEHS). Partition coefficient (log Pow) values are expected to be high for all compounds.
SUMMARY OF TOXICITY
No human or laboratory animal data providing insights into the toxicity of DIDS were originally available.
DIDS is not predicted to be irritating to the skin or eyes, or to be a skin sensitiser. This is supported by reassuring experimental data on DOS and DIDA and predicted data on DEHS. Experimental data obtained with DOS, DEHS and DIDA indicate a very low oral acute toxicity potential (LD50 5‑26 g/kg bw in mice and rats). In repeated dose studies at 10 mg/kg bw/day (DOS, 19-month dietary study in rats) or 1000 mg/kg bw/day (DIDA, 14-day study in rats), no adverse effects were seen. Adverse effects on the liver were observed in a study of 1000 mg/kg bw/day DEHS in rats, but these were judged to be of no/limited human relevance.
In QSAR analyses, DIDS and DEHS contain no structural alerts for micronucleus formation or chromosome aberrations, although a separate model suggests that equivocal evidence of chromosome aberration would be the likely outcome if a study was conducted with Chinese hamster ovary (CHO) cells. No evidence of mutagenic activity was seen in Ames tests with DEHS or DIDA. In addition for DIDA, equivocal experimental evidence of gene mutations (mouse lymphoma assay) and chromosome aberrations (in human lymphocytes) have been reported.
DIDS contains no structural alerts for carcinogenicity or reproductive/developmental toxicity. In the limited available experimental data set, no evidence of carcinogenic activity was seen with DOS or DEHS and no adverse effects on reproduction or development were reported in a study with DOS.
DATA MATRIX OF TARGET AND SOURCE COMPOUNDS
Target |
Source |
|||
DIDS |
DOS |
DEHS |
DIDA |
|
Diisodecyl sebacate |
Dioctyl sebacate |
Diethylhexyl sebacate |
Diisodecyl adipate |
|
|
Identification |
|||
Systematic name |
Bis(8-methylnonyl) sebacate |
Dioctyl sebacate |
Bis(2-ethylhexyl) sebacate |
Bis(8-methylnonyl) adipate |
CAS RN |
28473-19-0 |
2432-87-3 |
122-62-3 |
27178-16-1 |
EC Number |
249-047-0 |
219-411-3 |
204-558-8 |
248-299-9 |
Molecular formula |
C30H58O4 |
C26H50O4 |
C26H50O4 |
C26H50O4 |
Molecular weight |
482.78 g/mol |
426.67 g/mol |
426.67 g/mol |
426.67 g/mol |
Structure |
[See attachment] |
[See attachment] |
[See attachment] |
[See attachment] |
|
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Physico-Chemical Properties |
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Physical form |
Colourless liquid with mild odour |
No data |
Colourless liquid with mild odour |
Colourless liquid with mild odour |
Melting point |
-54 °C |
< -50 °C |
< -50 °C |
-63 °C |
Boiling point |
420 °C at 1013 hPa |
218 °C at 0.67 hPa |
256 °C at 6.67 hPa |
385 °C at 1018 hPa |
Relative density |
0.91 g/cm3at 20 °C |
0.91 g/cm3 at 25 °C |
0.91 g/cm3 at 25 °C |
0.92 g/cm3 at 15 °C |
Vapour pressure |
4.05 x 10-6 Pa [predicted] |
No data |
1.97 x 10-6 Pa [predicted] |
1.53 x 10-5 Pa |
Partition coefficient Log poct/wat |
> 6.5 |
3 – 10 [predicted] |
3 – 10 [predicted] |
10.1 [estimated] |
Solubility in water |
Insoluble: 9.5 x 10-2 mg/Lat 20 °C |
No data |
Insoluble in water |
Insoluble: 4.4 x 10-5 mg/L at 20 °C |
Flash point |
226 °C (closed cup) |
> 200 °C |
> 200 °C |
221 °C (closed cup) |
|
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Environmental Factors |
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Bioaccumulation |
Unlikely: BCF < 50 |
No data |
Unlikely: BCF < 110 |
Unlikely: BCF < 100 |
Biodegradation |
Readily biodegradable 79% after 28 days |
78.2% degraded after 3 wk |
65% degraded after 28 days |
Readily biodegradable 72-76% degraded after 28 days |
|
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Toxicokinetics |
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Absorption |
Low [predicted]
There is likely to be extensive absorption of the products of intestinal hydrolysis (diacid, alcohol) |
Low [predicted]
There is likely to be extensive absorption of the products of intestinal hydrolysis (diacid, alcohol) |
Low [predicted]
There is likely to be extensive absorption of the products of intestinal hydrolysis (diacid, alcohol) |
Low [predicted]
There is likely to be extensive absorption of the products of intestinal hydrolysis (diacid, alcohol) |
Distribution |
Based on high molecular weight, lipophilicity and low solubility, tissue distribution is expected to be low, although DIDS may concentrate in adipose tissue [predicted] |
Based on high molecular weight, lipophilicity and low solubility, tissue distribution is expected to be low, although DOS may concentrate in adipose tissue [predicted] |
Based on high molecular weight, lipophilicity and low solubility, tissue distribution is expected to be low, although DEHS may concentrate in adipose tissue [predicted] |
Based on high molecular weight, lipophilicity and low solubility, tissue distribution is expected to be low, although DIDA may concentrate in adipose tissue [predicted] |
Metabolism |
The structure of DIDS suggests that it will be metabolised by ester hydrolysis to form dicarboxylic acid and alcohol molecules, with potential for subsequent glucuronidation or sulfation [predicted] |
The structure of DOS suggests that it will be metabolised by ester hydrolysis to form dicarboxylic acid and alcohol molecules, with potential for subsequent glucuronidation or sulfation [predicted] |
The structure of DEHS suggests that it will be metabolised by ester hydrolysis to form dicarboxylic acid and alcohol molecules, with potential for subsequent glucuronidation or sulfation [predicted] |
The structure of DIDA suggests that it will be metabolised by ester hydrolysis to form dicarboxylic acid and alcohol molecules, with potential for subsequent glucuronidation or sulfation [predicted] |
Excretion |
The high molecular weight, low solubility and potential for conjugation during metabolism, are factors suggesting the possibility that any absorbed intact DIDS is likely to be excreted in the faeces, probably via the bile [predicted]
In reality, the expected extensive metabolism of diester is likely to yield low molecular weight species that are utilised or conjugated and excreted in the urine |
The high molecular weight, low solubility and potential for conjugation during metabolism, are factors suggesting the possibility that any absorbed intact DOS is likely to be excreted in the faeces, probably via the bile [predicted]
In reality, the expected extensive metabolism of diester is likely to yield low molecular weight species that are utilised or conjugated and excreted in the urine |
The high molecular weight, low solubility and potential for conjugation during metabolism, are factors suggesting the possibility that any absorbed intact DEHS is likely to be excreted in the faeces, probably via the bile [predicted]
In reality, the expected extensive metabolism of diester is likely to yield low molecular weight species that are utilised or conjugated and excreted in the urine |
The high molecular weight, low solubility and potential for conjugation during metabolism, are factors suggesting the possibility that any absorbed intact DIDA is likely to be excreted in the faeces, probably via the bile [predicted]
In reality, the expected extensive metabolism of diester is likely to yield low molecular weight species that are utilised or conjugated and excreted in the urine
|
|
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Toxicity Summary |
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Skin irritation |
Not irritating [predicted] |
Not irritating |
Not irritating |
Not irritating |
Eye irritation |
Not irritating [predicted] |
No data |
Not irritating [predicted] |
Not irritating |
Sensitisation |
Not sensitising [predicted] |
Not sensitising |
Not sensitising [predicted] |
Not sensitising |
Acute oral toxicity |
No data |
Low: LD50 9.5-17 g/kg bw in mice and rats |
Low: LD50 5-26 g/kg bw in mice and rats |
Low: LD50> 10 g/kg bw in mice and rats |
Repeated dose oral toxicity |
Low: NOAEL 300 mg/kg bw/day in male rats, based upon results from a 90 -day repeated-dose study. Observed adverse effect has no human relevance |
Low: NOAEL 10 mg/kg bw/day based on 19-month dietary study in rats (only tested dose) |
Low: LOAEL 1000 mg/kg bw/day in rats (only tested dose); observed adverse effect has limited or no human relevance |
Low: NOAEL 1000 mg/kg bw/day in rats based on 14-day study |
Genotoxicity |
|
|
|
|
Ames test |
Negative [predicted] |
No data |
Negative |
Negative |
Mammalian gene mutation |
No data [and QSAR model out of domain] |
No data |
No data |
Equivocal evidence of genotoxicity in a mouse lymphoma test |
Chromosomal aberrations/ micronuclei |
Equivocal evidence of chromosomal aberration expected in CHO cells [predicted] No structural alerts for micronuclei or chromosomal aberrations [predicted] |
No data |
Equivocal evidence of chromosomal aberration expected in CHO cells [predicted] No structural alerts for micronuclei or chromosomal aberrations [predicted] |
Equivocal evidence of chromosomal aberrations in human lymphocytes |
Carcinogenicity |
No structural alerts for carcinogenicity |
No evidence of carcinogenicity in rats when fed a diet containing 10 mg/kg bw/day DOS for 19 months |
No evidence of tumour-promoting activity in rats at 500 mg/kg bw/day |
No data |
Reproductive/ Developmental Toxicity |
Low: an OECD 414 study was conducted using DIDS as the test item. There were no effects attributed to the primary actions of the test item in foetuses and embryos examined, and thus the highest dose (1000 mg/kg bw/day) is considered to be NOAEL.
|
No apparent effects on reproduction or development in rats when fed a diet containing 10 mg/kg bw/day DOS for 19 months (four generations) |
No data
|
No data |
CONCLUSION
The source and target substances have very similar structures in respect of molar mass and commonality of key functional groups, and the target substance has no novel groups of concern. This, together with the similar expected toxicokinetics behaviour and products (as presented above) supports the read-across validity. In addition, the available data (test and predicted) indicate that the source and target substances have similar physico-chemical, fate and behaviour and (eco)toxicity profiles.
Based on the considerations above, it appears appropriate and justified to use data on the source compounds (DOS, DEHS and DIDA), where required, as part of a read-across strategy to help to predict the physico-chemical, fate and behaviour and (eco) toxicity characteristics of the target compound, DIDS.
References
ECHA (2013). Grouping of substances and read-across approach. Part 1: Introductory note. April 2013. Report no.: ECHA-13-R-02-EN. Owner company: European Chemicals Agency. http://echa.europa.eu/documents/10162/13628/read_across_introductory_note_en.pdf
OECD (2007). Organisation for Economic Co-operation and Development. Guidance on Grouping of Chemicals. Series on testing and assessment Number 80. ENV/JM/MONO(2007)28. OECD Environment Health and Safety Publications.http://www.oecd.org/officialdocuments/displaydocumentpdf?cote=env/jm/mono(2007)28&doclanguage=en
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