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EC number: 267-041-6 | CAS number: 67763-18-2
- 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
RDT oral (OECD guideline 408), rat NOAEL = 630/2187 (males/females) mg/kg bw/day (RA from CAS 103-23-1)
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented study report which meets basic scientific principles (no data on haematology, clinical chemistry, urinalysis and behavioural analysis).
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- no data on haematology and clinical chemistry
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: NCI Frederick Cancer Research Center, Frederick, Maryland
- Age at study initiation: 3 weeks old
- Housing: 5 per cage in solid bottom suspended polycarbonate cages equipped with disposable nonwoven fiber filter sheets and Aspen-bed hardwood chips as bedding
- Diet: powdered Wayne Lab Blox diet, ad libitum
- Water: available via an Edstrom automatic watering system, ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-31
- Humidity (%): 10-88
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): at least every 14 days
- Mixing appropriate amounts with (Type of food): chemical was mixed with aliquot of powdered Wayne Lab Blox animal feed, placing the mixture in a Petterson-Kelly twin-shell intensifier bar V-blender with the remainder of the feed and mix for 10 minutes
- Storage temperature of food: 4 °C for no longer than 14 days - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The amounts of the test substance in 12500 and 25000 ppm samples were determined by vapour phase chromatography. One-gram samples of each of the above mixtures were triturated twice with 50-mL portions of methanol. The supernatant solutions were combined and diluted to a volume of 100 mL and analyzed. The mean of the analytical concentration was usually within 10% of the theoretical.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
1600, 3100, 6300, 12500, 25000 ppm
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
females: 140, 271, 551, 1094, 2187 mg/kg bw/day; males: 160, 310, 630, 1250, and 2500 mg/kg bw/day
Basis:
other: actual ingested (recalculated based on food consumption). Only the corresponding values to 6300 ppm were given in the study report. The other doses were calculated with the mean food consumption used to calculate these given values. - No. of animals per sex per dose:
- 10 males and 10 females
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: doses used are based on an acute study and a 14 day study
(groups of five rats per sex were treated with five dose levels of the test substance in feed (up to 100000 ppm) for 14 days, followed by 1 day of observation with control diet. 1 group per sex were maintained as untreated controls. All surviving animals were killed after 15 days. - Observations and examinations performed and frequency:
- CAGE SIDE & CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- no specifics given on how feed consumption was observed - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- one female (1600 ppm) died,
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- one female (1600 ppm) died,
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- dose-related body weight depression up to 18% (males); no effects in females
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
One female rat recieving 1600 ppm died, but its death was not considered to be compound-related.
BODY WEIGHT AND WEIGHT GAIN
Weight gain depression was 11% or more for male rats fed 12500 ppm or 25000 ppm.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No compound-related reduction in feed consumption were observed.
HISTOPATHOLOGY: NON-NEOPLASTIC
No compound-related histopathological effects were observed. - Dose descriptor:
- NOAEL
- Effect level:
- 630 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: decreased body weight at 1250 mg/kg bw/day
- Dose descriptor:
- NOAEL
- Effect level:
- 6 300 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: decreased body weight at 12500 ppm
- Dose descriptor:
- LOAEL
- Effect level:
- 1 250 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: decreased body weight
- Dose descriptor:
- LOAEL
- Effect level:
- 12 500 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: decreased body weight
- Dose descriptor:
- NOAEL
- Effect level:
- 2 187 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no effects observed at the highest dose
- Dose descriptor:
- NOAEL
- Effect level:
- 25 000 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no effects observed at the highest dose
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Additional information
Justification for grouping of substances and read-across
There are only limited data available on repeated dose toxicity of Diisooctadecyl malate (CAS 67763-18-2). In order to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substance was conducted. In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across). Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.
Overview of repeated dose toxicity:
CAS |
Chemical name |
Molecular weight[g/mol] |
Repeated dose toxicity Oral |
Repeated dose toxicity Inhalation |
Repeated dose toxicity Dermal |
67763-18-2 (a) |
Diisooctadecyl malate |
639.06 |
RA: CAS 103-23-1 |
-- |
-- |
103-23-1 (b) |
Bis(2-ethylhexyl) adipate |
370.57 |
Experimental result: NOAEL = 630/2187 mg/kg bw/day (rat) |
--
|
-- |
(a) The substance subject to registration is indicated in bold font.
(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.
The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Diisooctadecyl malate (CAS 67763-18-2). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).
Discussion
No data on repeated dose toxicity is available with Diisooctadecyl malate (CAS 67763-18-2). Therefore, read across from the structurally analogue substances Bis(2-ethylhexyl) adipate (CAS 103-23-1) was applied.
Repeated dose toxicity: Oral
CAS 103-23-1
A reliable subchronic oral toxicity study equivalent or similar to OECD 408 was performed with Bis(2-ethylhexyl) adipate (CAS 103-23-1) in Fischer 344 rats at dose levels of 1600, 3100, 6300, 12500 and 25000 ppm for a period of 90 days (NTP, 1982). Ten animals per sex and dose received the test substance daily via diet, whereas a similar constituted control group was administered the plain diet. No signs of toxic effects and no mortality were observed in any of the animals during the study period. Body weight gain was adversely reduced in males at 12500 and 25000 ppm. Average food consumption was not altered between treated and control groups of both genders. No adverse effects were noted at histopathological examination in all animals. Clinical chemistry and haematological parameters were not reported in this study. Based on these results, a NOAEL of 6300 ppm was derived for male rats, corresponding to an actual ingested dose of 630 mg/kg bw/day. In female rats, the NOAEL was set at 25000 ppm, which was equivalent to a dose of 2187 mg/kg bw/day.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from structural analogues. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose.
Justification for classification or non-classification
According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to Diisooctadecyl malate (CAS 67763-18-2), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.
Therefore, based on the analogue read-across approach, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.
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.
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