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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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP - guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
- Reference Type:
- publication
- Title:
- Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test of Bis(2-ethylhexyl) azelate by Oral Administration in Rats
- Author:
- Shirota, M
- Year:
- 2 004
- Bibliographic source:
- Toxicity Testing Reports of Environmental Chemicals, 11, 287-320
- Reference Type:
- secondary source
- Title:
- Bis(2-ethylhexyl) azelate
- Author:
- OECD
- Year:
- 2 006
- Bibliographic source:
- SIDS Initial Assessment Report for SIAM 22, Paris, France, 18-21 April, 2006
- Reference Type:
- secondary source
- Title:
- Diesters Category of the Aliphatic Esters Chemicals (Test Plan and Robust Summaries for Substances in the HPV Test Plan)
- Author:
- US-EPA (American Chemistry Council's Aliphatic Esters Panel)
- Year:
- 2 010
- Bibliographic source:
- High Production Volume (HPV) Chemical Challenge Program (201-16837A and 201-16837B)
Materials and methods
Test guideline
- 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
Test material
- Reference substance name:
- 103-24-2 (analytical purity 77.2%)
- IUPAC Name:
- 103-24-2 (analytical purity 77.2%)
- Details on test material:
- - Name of test material (as cited in study report): Bis(2-ethylhexyl)nonanedioate
- Analytical purity: 77.2%
- Impurities (identity and concentrations):
Bis(2-ethylhexyl)glutarate 2.2%,
Bis(2-ethylhexyl)adipate 2.4%,
Bis(2-ethylhexyl)pimelate 2.8%,
Bis(2-ethylhexyl)suberate 3.8%,
Bis(2-ethylhexyl)sebacate 3.3%,
Bis(2-ethylhexyl) 1-,9-nonamethylenedicarboxylate 5.3%,
Bis(2-ethylhexyl)1-,10-decamethylenedicarboxylate 0.6%,
Bis(2-ethylhexyl)1-,11-undecamethylenedicarboxylate 0.3%
- Lot/batch No.: N-31101
Constituent 1
Test animals
- 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
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on 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 - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: up to 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as Day 0 of pregnancy
- After successful mating each pregnant female was caged: Individually - 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
Doses / concentrations
- 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
- Details on study design:
- - Dose selection rationale: The concentration was determined based on the result of pre-test.
The concentrations used in the pre-test were 250, 500 and 1000 mg/kg bw/day. There were no differences between the 250 and higher concentration treatment groups. This is the reason why the highest concentration used in this test was 250 mg/kg bw/day.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily before and after dosing
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at 13:00-16:00 before dosing and on Days 7, 14, 21, 28, 35 and 42 of the treatment period using scoring systems. In the detailed clinical observations, the animals were observed for about 20 min to determine changes in appearance, gait, posture, locomotor activity, grooming, respiratory rate, palpebral opening, and presence of vocalization, tail reaction, stereotype, tremor, convulsion, piloerection and abnormal behavior.
BODY WEIGHT: Yes
- Time schedule for examinations: on Days 1 (before dosing), 7, 14, 21, 28, 35, 42 of treatment and prior to necropsy in males and on Days 1 (before dosing), 7 and 14, 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:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Food consumption was not determined during the mating period in males and females.
OTHER:
Neurobehavioral tests, such as Preyer's reflex, pupillary reflex, pain reaction, withdrawal reflex, eyelid reflex and righting reflex, were determined for 5 animals/sex/dose on Day 42 of treatment in males and on day 4 of lactation in females.
Haematological and blood biochemical examination:
Blood samples were collected from the abdominal aorta after overnight starvation on next day of the last administration. - Oestrous cyclicity (parental animals):
- Parameters examined in P female parental generation:
estrous cycle, precoital interval, frequency of vaginal estrus cycle and gestation length - Sperm parameters (parental animals):
- Parameters examined in P male parental generation:
testis weight, epididymis weight, histopathology of male reproductive organs - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on Day 4 post partum: yes
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weight: Brain, heart, liver, kidney, spleen, adrenal, thymus, testis and epididymis
Microscopic examination: 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. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations. - Statistics:
- Dunnett's test for continuous data, and Mann-Whitney' U-test and Fisher' test for discrete data
- Reproductive indices:
- copulation index (no. of copulated pairs/no. of mated pairs x 100),
fertility index (no. of pregnant animals/no. of animals with successful copulation x 100),
gestation index (no. of females with live pups/no. of pregnant females x 100),
implantation index (no. of implantation sites/no. of corpora lutea x 100),
delivery index (no. of pups born/no. of implantation sited x 100) - Offspring viability indices:
- birth index (no. of live pups on day 0/no. of implantation sites x 100),
live birth index (no. of live pups on Day 0/no. of pups born x 100),
viability index (no. of pups alive on Day 4 of lactation/no. of pups born x 100)
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects 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):
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: impaired BW gain in males
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- 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)
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: prolongation of estrous cycle
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
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 FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight gain was suppressed in males of the 1000 mg/kg bw/day-treated group. No effects were observed in males and females of the test substance-treated groups.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
At 1000 mg/kg bw/day, the test substance altered the length of estrous cycle.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No effects were observed in sperm parameters in males.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No effects observed on reproductive performance in males and females given each dose.
ORGAN WEIGHTS (PARENTAL ANIMALS)
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 chapter for repeated dose toxicity).
GROSS PATHOLOGY (PARENTAL ANIMALS)
No adverse effects were observed for males and females.
HISTOPATHOLOGY (PARENTAL ANIMALS)
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 chapter for repeated dose toxicity).
OTHER FINDINGS (PARENTAL ANIMALS)
An increase in albumin/globulin 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 albumin/globulin ratio noted in females at 300 mg/kg bw/day was not considered as an adverse effect because of no accompanying changes (see chapter for repeated dose toxicity).
Effect levels (P0)
open allclose all
- Dose descriptor:
- LOAEL
- Remarks:
- reproduction
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: estrous cycle
- Dose descriptor:
- NOAEL
- Remarks:
- reproduction
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: estrous cycle
- Dose descriptor:
- NOAEL
- Remarks:
- reproduction
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: overall effects
- 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
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
No treatment related effect was observed on total No. of pups born, No. of males, No. of females, sex ratio, live pups, stillbirth and runt on post-natal Day (PND) 0 and total No. of live pups and sex ratio on PND 4. Viability index was unaffected. Survival of the pups from PND 0 - 4 remained unaffected in all treatment groups.
BODY WEIGHT (OFFSPRING)
No effect on group mean litter weight, total litter weight, male litter weight and female litter weight on PND 0 and PND 4.
GROSS PATHOLOGY (OFFSPRING)
No substance related gross external and internal findings were observed in any of the treated groups.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1: Reproductive parameters
Dose(mg/kg bw/day) |
|
0 |
100 |
300 |
1000 |
No.of female animals: |
|
13 |
13 |
13 |
13 |
No.of animals which type of |
|
3 |
5 |
5 |
8 |
Length of estrous cycle (days) |
|
||||
|
mean |
4.1 |
4.3 |
4.3 |
4.6* |
|
SD |
0.5 |
0.3 |
0.4 |
0.5 |
No. of mated pairs: |
|
13 |
13 |
13 |
13 |
No. of copulated pairs: |
|
13 |
13 |
13 |
13 |
Copulation index (%) |
|
100 |
100 |
100 |
100 |
No. of pregnant females |
|
12 |
11 |
11 |
12 |
Fertility index (%) |
|
92.3 |
84.6 |
84.6 |
92.3 |
Pairing day until copulation |
|
||||
|
mean |
3.4 |
3.0 |
2.5 |
1.8 |
|
SD |
3.3 |
3.5 |
1.1 |
1.2 |
Frequency of vaginal estrus during mating period |
|
||||
|
mean |
1.0 |
1.0 |
1.0 |
1.0 |
|
SD |
0.0 |
0.0 |
0.0 |
0.0 |
No. of pregnant females with pups alive: |
|
12 |
11 |
11 |
12 |
Gestation index (%) |
|
100.0 |
100.0 |
100.0 |
100.0 |
Gestation length (days) |
|
||||
|
mean |
22.6 |
22.4 |
22.7 |
22.9 |
|
SD |
0.5 |
0.5 |
0.5 |
0.3 |
No. of corpora lutea |
|
||||
|
mean |
16.2 |
16.4 |
16.6 |
17.4 |
|
SD |
1.3 |
1.7 |
1.9 |
2.9 |
No.of implantation site |
|
||||
|
mean |
15.5 |
15.8 |
16.1 |
14.9 |
|
SD |
1.2 |
1.7 |
1.7 |
4.0 |
Implantation index (%) |
|
||||
|
mean |
96.0 |
96.8 |
96.9 |
85.7 |
|
SD |
5.2 |
5.7 |
4.0 |
21.0 |
Day 0 of lactation |
|
||||
No.of pups born |
|
||||
|
mean |
13.8 |
14.9 |
14.5 |
12.3 |
|
SD |
2.0 |
2.7 |
1.9 |
5.1 |
Delivery index (%) |
|
||||
|
mean |
89.3 |
93.6 |
89.8 |
78.3 |
|
SD |
11.2 |
8.4 |
6.2 |
24.4 |
No.of pups alive |
|
||||
|
mean |
13.6 |
13.6 |
13.5 |
9.9 |
|
SD |
2.2 |
4.1 |
2.4 |
5.3 |
Birth index (%) |
|
||||
|
mean |
87.7 |
86.0 |
83.8 |
65.1 |
|
SD |
12.7 |
22.1 |
9.5 |
29.6 |
Live birth index (%) |
|
|
|
|
|
|
mean |
98.1 |
92.4 |
93.5 |
84.1 |
|
SD |
4.8 |
23.0 |
10.6 |
28.0 |
Pups weight (g) |
|
||||
Male |
mean |
7.2 |
6.9 |
7.2 |
6.8 |
|
SD |
0.5 |
0.8 |
0.9 |
0.7 |
Female |
mean |
6.7 |
6.5 |
6.8 |
6.5 |
|
SD |
0.7 |
0.8 |
0.9 |
0.8 |
Sex ratio on day 0 of lactation (no. of male pups/total no. of pups) |
|
||||
|
mean |
54.1 |
47.0 |
45.9 |
48.5 |
|
SD |
11.5 |
12.0 |
17.6 |
24.5 |
Day 4 of lactation |
|
||||
No.of pups alive |
|
||||
|
mean |
13.1 |
14.2 |
13.7 |
9.6 |
|
SD |
3.1 |
2.7 |
1.9 |
5.2 |
Viability index (%) |
|
||||
|
mean |
95.6 |
97.7 |
98.1 |
97.8 |
|
SD |
13.1 |
7.4 |
5.9 |
3.8 |
Pups weight (g) on day 4 of lactation |
|
||||
Male |
mean |
11.6 |
11.0 |
11.7 |
10.9 |
|
SD |
1.0 |
2.3 |
2.5 |
2.4 |
Female |
mean |
10.9 |
10.5 |
11.3 |
11.0 |
|
SD |
1.5 |
2.2 |
2.4 |
0.7 |
Sex ratio on day 4 of lactation (no. of male pups/total no. of pups) |
|
||||
|
mean |
53.5 |
44.1 |
47.3 |
48.8 |
|
SD |
11.3 |
8.0 |
17.9 |
24.5 |
* significant difference from control, p < 0.05
Applicant's summary and conclusion
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.