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EC number: 945-069-6 | 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
Description of key information
In a study according to OECD 422 male and female rats were exposed to bis(2-ethylhexyl) azelate by gavage during 14 days before mating, 28 days afterwards (males) or during pregnancy until day 4 of lactation. There was no mortality and clinical signs did not differ between treated and control animals. Body weight gain was suppressed in males at 1000 mg/kg bw from day 28 onwards. No adverse effects on food consumption, haematology and behavioural assessment were seen. Clinical chemistry revealed a dose related increase in albumin/globulin (A/G) ratio in males at 1000 mg/kg bw and in females at 300 and 1000 mg/kg bw. The effect in females at 300 mg/kg bw was not accompanied by histopathological changes. Decreases in total protein, creatinine and calcium were observed in females at 1000 mg/kg bw/day. There were increases in relative weight of liver and absolute and relative weights of kidney for males and increases in relative weights of liver and kidney for females were observed in the 1000 mg/kg. For the liver histopathology a tendency of increase in hypertrophy of centrilobular hepatocytes and a reduction in the grade of periportal fatty change was observed in males of the 1000 mg/kg bw (not in females)
Based on these findings the NOAEL for parental effects is set at 300 mg/kg bw.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP - guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crj:CD(SD)IGS
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Yokohama, Japan
- Age at study initiation: 10 weeks
- Housing: Metal mesh cage
- Diet: ad libitum, CE-2 from CLEA Japan, Inc., Meguro, Japan
- Water: ad libitum, tap water
- Acclimation period: about 3 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.0 - 25.5
- Humidity (%): 49.5 - 73.0
- Air changes: 15 times/day
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dosing solution was prepared more than once a week and stored at room temperature in the dark for 7 days. The stability for 8 days was verified by GC.
VEHICLE
- Amount of vehicle (if gavage): 5 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dosing solution was mixtured with n-hexane and concentrations were analyzed by GC.
- Duration of treatment / exposure:
- Males: 14 days before mating, 28 days afterwards
Females: total of 42-53 days beginning 14 days before mating to day 4 of lactation - Frequency of treatment:
- 7 days/week
- Remarks:
- Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 13
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily before and after treatment
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at 13:00-16:00 on Days 7, 14, 21, 28, 35 and 42 of the treatment period using scoring systems.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were determined on Days 1, 7, 14, 21, 28, 35, 42 of treatment and prior to necropsy in males and on Days 1, 7, 14 and 21 of treatment, Days 0, 7, 14 and 20 of gestation, Days 0 and 4 of lactation and prior to necropsy in females.
FOOD CONSUMPTION: Yes
- Time schedule: Days 1-2, 7-8, 14-15, 29-30, 35-36 and 41-42 of treatment in males, and on Days 1-2, 7-8 and 14-15 of the treatment period, Days 0-1, 7-8, 14-15 and 20-21 of gestation and day 3-4 of lactation in females. Food consumption was not determined during the mating period in males and females.
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were collected from the abdominal aorta after overnight starvation on
next day of the last administration.
- Animals fasted: Yes
- How many animals: All
- Following parameters were checked: red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cells (WBC), neutrophils, eosinophils, basophils, monocytes, lymphocytes, platelets, prothrombin time (PT), activated partial thromboplastin time (APTT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples were collected from the abdominal aorta after overnight starvation on
next day of the last administration.
- Animals fasted: Yes
- How many animals: All
- Following parameters were checked: total protein, albumin, albumin/globulin ratio (A/G ratio), blood urea nitrogen (BUN), creatinine, glucose, total cholesterol, triglycerides, alkaline phosphatase (ALP), alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, total bilirubin, inorganic phosphor, Ca, Na, K, Cl
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on Day 42 of treatment in males and on Day 4 of lactation in females.
- Dose groups that were examined: 5 animals/sex/dose
- Battery of functions tested: Preyer's reflex, pupillary reflex, pain reaction, withdrawal reflex, eyelid reflex and righting reflex - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Organ weights: Brain, heart, liver, kidney, spleen, adrenal, thymus, testis and epididymis
HISTOPATHOLOGY: Yes
Testis, epididymis and ovary of all animals at all doses, and
brain, pituitary, thymus, thyroid, parathyroid, adrenal, spleen, heart, stomach,
liver, duodenum, jejunum, ileum, cecum, colon, rectum, trachea, lung, kidney, urinary
bladder, femur, spinal cord, mesentery lymph node, submandibular gland, sciatic nerve,
bone marrow, prostate, seminal vesicle, uterus and vagina of 5 males and females at 0
and 1000 mg/kg bw/day. - Statistics:
- Statistical methods: Dunnett's test for continuous data, and Mann-Whitney' U-test and Fisher' test for discrete data.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: impaired BW gain in males
- 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 specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw: decrease in white blood cells
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: increase in albumin/globulin ratio in males/females, decrease in total protein and Ca in females; 300 mg/kg bw/day: increase in albumin/globulin ratio in females
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day group: increase in rel. liver and kidney weight in males and females (non adverse)
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw:/day: hepatocellular hypertrophy and periportal fatty change in males, (non adverse)
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: There was no mortality related to the test substance treatment. No changes were observed on general clinical observation, nor were scores obtained by detailed clinical observations between control and the test substance-treated groups.
BODY WEIGHT AND WEIGHT GAIN
Body weight gain was suppressed in males of the 1000 mg/kg bw/day-treated group (see Table 1)
FOOD CONSUMPTION
No effects were observed in males and females of the test substance-treated groups.
HAEMATOLOGY
No effects were observed in males of the test substance-treated groups. A decrease in white blood cells (WBC) and a shorter activated partial thromboplastin time were observed in females of the 1000 mg/kg bw/day dose group. But these change were not considered as adverse effects because of no accompanying changes. A decrease in WBC was observed in females of the 1000 mg/kg bw/day dose group.
CLINICAL CHEMISTRY
An increase in albumin/globulin (A/G) ratio was found in males at 1000 mg/kg bw/day and in females at 300 mg/kg bw/day and higher. Decreases in total protein, creatinine and calcium were observed in females at 1000 mg/kg bw/day. The increase in A/G ratio noted in females at 300 mg/kg bw/day was not considered as an adverse effect because of no accompanying changes (see Table 2). Decreases in glucose and alkaline phosphatase observed in females of 100 mg/kg bw/day group and 300 mg/kg bw/day, respectively, were incidential observations and thus considered non-adverse.
NEUROBEHAVIOUR
No neurobehavioural abnormalities were observed in the test substance-treated groups.
ORGAN WEIGHTS
Increases in a relative weight of liver and absolute and relative weights of kidney for males and increases in relative weights of liver and kidney for females were observed in the 1000 mg/kg bw/day group (see Table 3).
GROSS PATHOLOGY
No adverse effects were observed for males and females.
HISTOPATHOLOGY: NON-NEOPLASTIC
Tendency of increase in hypertrophy of centrilobular hepatocytes and a reduction in the grade of periportal fatty change were observed in males of the 1000 mg/kg bw/day group (see Table 4). - Dose descriptor:
- LOAEL
- Remarks:
- systemic
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: clinical chemistry; body weight; organ weight
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: clinical chemistry; body weight; organ weight
- Critical effects observed:
- not specified
Reference
Table 1: Body weight gain in males
Days of treatment |
|
dose [mg/kg bw/day] |
|
|
|
|
|
0 |
100 |
300 |
1000 |
males |
|
13 |
13 |
13 |
13 |
1-7 |
mean |
23.6 |
27.3 |
19.9 |
21.5 |
|
SD |
10.1 |
7.5 |
11.9 |
4.6 |
7-14 |
mean |
27.4 |
26.1 |
23.4 |
27.3 |
|
SD |
7.9 |
6.8 |
6.1 |
5.6 |
14-21 |
mean |
20.4 |
24.1 |
22.1 |
21.2 |
|
SD |
5.9 |
4 |
6.7 |
8.5 |
21-28 |
mean |
24.4 |
25.2 |
24.1 |
20.8 |
|
SD |
8.8 |
4 |
7.9 |
5.4 |
28-35 |
mean |
25.4 |
24.5 |
22.1 |
17.3** |
|
SD |
5.3 |
5 |
4.3 |
5 |
35-42 |
mean |
22.5 |
22.7 |
21 |
13.1** |
|
SD |
6.2 |
4.7 |
5.4 |
6 |
Table 2: Altered clinical chemistry data
|
|
dose [mg/kg bw/day] |
|
||
|
|
0 |
100 |
300 |
1000 |
males |
|
13 |
13 |
13 |
13 |
A/G ratio |
mean |
1.18 |
1.16 |
1.21 |
1.28* |
|
SD |
0.09 |
0.1 |
0.11 |
0.09 |
females |
|
12 |
10 |
9 |
11 |
A/G ratio |
mean |
1.26 |
1.32 |
1.41* |
1.45** |
|
SD |
0.07 |
0.08 |
0.16 |
0.13 |
Creatinine [mg/dL] |
mean |
0.7 |
0.7 |
0.8 |
0.6** |
|
SD |
0.1 |
0 |
0.1 |
0.1 |
T.protein [g/dL] |
mean |
5.4 |
5.4 |
5.5 |
5.1** |
|
SD |
0.2 |
0.2 |
0.3 |
0.2 |
Ca [mg/dL] |
mean |
9.8 |
9.9 |
9.8 |
9.40** |
|
SD |
0.2 |
0.3 |
0.4 |
0.3 |
Table 3: Selected organ weights
|
|
|
dose [mg/kg bw/day] |
|
||
|
|
|
0 |
100 |
300 |
1000 |
males |
|
|
13 |
13 |
13 |
13 |
liver |
absolute [g] |
mean |
14.22 |
15.07 |
14.19 |
15.48 |
|
|
SD |
161.00 |
1.66 |
1.14 |
1.34 |
|
relative [%] |
mean |
2.86 |
2.99 |
2.95 |
3.27** |
|
|
SD |
0.16 |
0.26 |
0.17 |
0.21 |
kidney |
absolute [g] |
mean |
3.23 |
3.23 |
3.31 |
3.64** |
|
|
SD |
0.29 |
0.30 |
0.22 |
0.29 |
|
relative [%] |
mean |
0.65 |
0.64 |
0.69 |
0.77** |
|
|
SD |
0.06 |
0.07 |
0.04 |
0.06 |
females |
|
|
12 |
10 |
10 |
11 |
liver |
absolute [g] |
mean |
11.27 |
10.71 |
11.50 |
12.34 |
|
|
SD |
1.22 |
0.70 |
1.69 |
1.28 |
|
relative [%] |
mean |
3.53 |
3.51 |
3.70 |
3.92** |
|
|
SD |
0.31 |
0.22 |
0.27 |
0.24 |
kidney |
absolute [g] |
mean |
2.09 |
1.99 |
2.20 |
2.28 |
|
|
SD |
0.18 |
0.21 |
0.19 |
0.22 |
|
relative [%] |
mean |
0.65 |
0.66 |
0.72 |
0.72* |
|
|
SD |
0.06 |
0.07 |
0.12 |
0.04 |
Table 4: Histopathological changes
|
|
|
dose [mg/kg bw/day] |
|
||
|
|
|
0 |
100 |
300 |
1000 |
males |
|
|
5 |
5 |
5 |
12 |
liver |
hypertrophy, hepatocyte, centrilobular |
very slight |
0 |
0 |
0 |
5* |
|
Fatty change periportal |
very slight |
2 |
2 |
5 |
5 |
|
|
slight |
3 |
2 |
0 |
0 |
|
|
moderate |
0 |
1 |
0 |
0 |
|
Total incidence |
|
5/5 |
5/5 |
5/5 |
5/12** |
* significant difference from control; p>0.05
** significant difference from control; p>0.01
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 300 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- based on a structural analogue that is expected to represent the effects of the substance
- System:
- hepatobiliary
- Organ:
- liver
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 - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The study available is on the analogue bis(2-ethylhexyl) azelate. The effects of this analogue (C8) are considered to represent potential effects of diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid, as their toxicokinetic behaviour (including absorption) is expected to be very similar. Based on its starting materials this analogue is also expected to represent a worst case.
Justification for classification or non-classification
Based on the outcome of the available studies on the analogue substances, no classification for diesters of alcohols, C7-9-iso-, C8-rich, 2-ethylhexyl and nonanedioic acid is considered according to EC No 1272/2008.
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