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EC number: 211-020-6 | CAS number: 627-93-0
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- This IUCLID for dimethyl adipate is compiled using data from the substance itself, a structurally related compound (dimethyl glutarate) and a mixture of dibasic esters (dimethyl adipate, succinate and glutarate). The toxicity of each of these substances is similar and the document attached justifies why data on the category members can be used to support the data gaps for dimethyl adipate.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 998
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Deviations:
- yes
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EU Method B.34 (One-Generation Reproduction Toxicity Test)
- Deviations:
- yes
- Principles of method if other than guideline:
- - Inhalation exposure.
- Male rats were also exposed until end of lactation period.
- Female rats were not exposed from gestation day 19 through postpartum day 3. - GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of dimethyl adipate, dimethyl glutarate and dimethyl succinate
- IUPAC Name:
- Reaction mass of dimethyl adipate, dimethyl glutarate and dimethyl succinate
- Details on test material:
- See information in the field "Confidential details on test material"
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Kingston, NY;
- Age at study initiation: (P) 4 wks
- Housing: individually, except during mating (1 male, 1 female)
- Diet (e.g. ad libitum): a libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 40 - 70%
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- other: inhalation of vapor at lower (0.0, 0.16 and 0.40 mg/L) doses; inhalation of aerosol at highest dose (1mg/L)
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1.4 m³ stainless steel and glass NYU-style inhalation chamber
- System of generating particulates/aerosols: vapour generation: flash-evaporation in a tube maintained at 250-300°C; aerosol vapour: nebulizer
- Air flow rate:300 L/min
TEST ATMOSPHERE
- Brief description of analytical method used: sample collection: in acetone-filled impingers; analysis method: GC-FID
- Samples taken from breathing zone: yes - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 5 days
- Proof of pregnancy: vaginal plug day 1 of pregnancy
- After successful mating each pregnant female was caged (how): individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of atmospheric DBE were taken from the rat breathing zone at approximately 60-minute intervals by drawing calibrated volumes of chamber atmosphere through fritted glass midget impingers containing acetone. Samples were analyzed using a Hewlett-Packard Model 5710 Gas Chromatograph (GC) equipped with a flame ionization detector. DBB was chromatographed isothermally at 150°C on a 3 ft x 2 mm ID glass column packed with 10% SP-1000 on Chromasorb W-AW 100/120 mesh.
Chamber concentrations were determined by comparing the chamber sample GC response with that obtained from standard samples prepared by quantitative dilution of DBE in acetone. The DBE chamber concentration was calculated after measuring the peak area of the largest DBE component, dimethyl glutarate. In addition, the relative amounts of the 3 largest DBE components (dimethyl-glutarate, -adipate, and -succinate) were qualitatively compared for each sample. - Duration of treatment / exposure:
- pre-breeding: 6 h per day
breeding, gestation, lactation: 6 h per day; - Frequency of treatment:
- pre-breeding: 5 days per week, 14 weeks;
breeding, gestation, lactation: 7 days per week, 8 weeks;
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/L air (nominal)
- Dose / conc.:
- 0.16 mg/L air (nominal)
- Dose / conc.:
- 0.4 mg/L air (nominal)
- Dose / conc.:
- 1 mg/L air (nominal)
- No. of animals per sex per dose:
- 20 males; 20 females;
- Control animals:
- yes, concurrent no treatment
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No
OTHER:
Mating performance, fertility, gestation length, and lactation performance were assessed. - Oestrous cyclicity (parental animals):
- no data
- Sperm parameters (parental animals):
- no data
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, viability, weight - Postmortem examinations (parental animals):
- All parental animals were sacrificed by exanguation under chloroform anesthesia and examined for gross anatomic abnormalities. Additionally, the nasal tissues were examined histologically; other tissues were examined grossly and saved. Mean organ and organ-to-body ratios were calculated for the brain, heart, lungs, liver, spleen, kidneys, testes and thymus.
- Postmortem examinations (offspring):
- Ten 21-day old arbitrarily selected pups of each sex per dose group were sacrificed by exanguination under chloroform anesthesia and examined for gross anatomic abnormalities. Mean organ and organ-to-body ratios were calculated for the brain, liver, kidneys, and testes.
- Statistics:
- For parental organ and body weight analyses, data were statistically analyzed by a one-way ANOVA. When the ratio of variance (F) indicated a significant group variation, test groups were compared with appropriate control group by least significant difference test for body weight data and by Dunnett's test for organ and final body weight data. Litter data were analyzed by Mann-Whitney U-test. Significance for statistical tests was judged at the 0.05 probability level.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weights were decreased in the 0.40 mg/L group female rats during the last week of the study. Weights were slightly decreased in male and female rats in the 1.0 mg/L group starting around the seventh week of the study.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathologic evaluation of parental generation rat nasal tissues showed squamous metaplasia primarily in the olfactory epithelium in all groups exposed to DBE. The nasal effect was minimal in the 0.16 mg/L group rats and of mild to moderate severity in the 0.40 and 1.0 mg/L groups. The squamous metaplasia was characterized by a flattening and pavementing of epithelial cells which replaced the normal architecture of olfactory epithelium. In some cases, particularly in the 0.40 and 1.0 mg/L rats, this squamous change was accompanied by a very minimal to mild suppurative inflammation. The squamous metaplasia was present primarily in the olfactory epithelium of the dorsal meatus, along the dorsal portion of the nasal septum, and on the tips of the ecto- and endoturbinates in the nasal cavity. There was also an increase in squamous metaplasia of the respiratory epithelium in the nasal cavity in the high-dose rats. The severity of the lesions ranged from absent-to-minimal up to moderate in some rats. One male rat in the 1.0 mg/L group had a meningeal sarcoma surrounding the olfactory region of the brain. Because the tumor did not communicate with the nasal cavity and the tumor cell type was unrelated to any nasal epithelial cell types, the tumor was considered to be unrelated to inhalation of DBE.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One male rat in the 1.0 mg/L group had a meningeal sarcoma surrounding the olfactory region of the brain. Because the tumor did not communicate with the nasal cavity and the tumor cell type was unrelated to any nasal epithelial cell types, the tumor was considered to be unrelated to inhalation of DBE.
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No treatment-related differences were observed between the control and test groups with regard to male or female fertility, gestation length, litter sizes, viability, or lactation performance.
Details on results (P0)
Body weights were decreased in the 0.40 mg/L group female rats during the last week of the study. Weights were slightly decreased in male and female rats in the 1.0 mg/L group starting around the seventh week of the study. No unusual signs or behaviours that could be associated with exposure to DBE were seen in rats in any of the treated groups. Parental rats in the 1.0 g/L group showed wet fur during exposures from aerosol deposition. The fur dried about 2 hours after exposure.
REPRODUCTION PARAMETERS
No treatment-related differences were observed between the control and test groups with regard to male or female fertility, gestation length, litter sizes, viability, or lactation performance. A slight but statistically significant decrease in viability index at birth (number of pups born alive per number of pups born) was observed in the 0.16 mg/L DBE group but this was considered to be unrelated to DBE exposure because it was not seen at either of the two higher exposure concentrations. All pups delivered by both DBE-exposed and control rats appeared outwardly normal. Body weights at birth and weaning (21 days pp) were significantly lower in the 1.0 mg/L group. The fertility rate in the control group was lower than that of the test groups (60% versus 75 to 90% for the test groups) and is low compared to historical rates for this laboratory. One potential contributing factor to the low fertility rate in the control group is that there were some males that never had the opportunity to mate with a subsequently proven fertile female; three of these males were in the control group, three in the 0.4 mg/L group, and two were in the 0.16 mg/L group. On the other hand all the males in the 1 mg/L group were mated with females who were subsequently proven to be fertile. Although the cause is uncertain, the control group low fertiIity rate did not impact the toxicity evaluation since the fertility rate in the DBE-exposed groups was well within historical limits.
PATHOLOGY
No gross pathologic changes were seen in any of either the parental rats or their offspring. Histopathologic evaluation of parental generation rat nasal tissues showed squamous metaplasia primarily in the olfactory epithelium in all groups exposed to DBE. The nasal effect was minimal in the 0.16 mg/L group rats and of mild to moderate severity in the 0.40 and 1.0 mg/L groups. The squamous metaplasia was characterized by a flattening and pavementing of epithelial cells which replaced the normal architecture of olfactory epithelium. In some cases, particularly in the 0.40 and 1.0 mg/L rats, this squamous change was accompanied by a very minimal to mild suppurative inflammation. The squamous metaplasia was present primarily in the olfactory epithelium of the dorsal meatus, along the dorsal portion of the nasal septum, and on the tips of the ecto- and endoturbinates in the nasal cavity. There was also an increase in squamous metaplasia of the respiratory epithelium in the nasal cavity in the high-dose rats. The severity of the lesions ranged from absent-to-minimal up to moderate in some rats. One male rat in the 1.0 mg/L group had a meningeal sarcoma surrounding the olfactory region of the brain. Because the tumor did not communicate with the nasal cavity and the tumor cell type was unrelated to any nasal epithelial cell types, the tumor was considered to be unrelated to inhalation of DBE.
ORGAN WEIGHTS
In parental rats, liver-to-body weight ratios were slightly lower than the controls in the rats exposed to either 0.40 and 1.0 mg/L. Other incidental differences between test and control rats included slight decreases in absolute heart and kidney weights in female rats in the 0.40 and 1.0 mg/L groups. A slight decrease in absolute spleen weight and a slight increase in relative brain weight were observed in females in the 1.0 mg/L group. These differences were not dose-related and may have been related to the slight body weight differences between the test and control groups and were considered of minimal biological significance.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEC
- Remarks:
- for systemic toxicity effects
- Effect level:
- >= 0.16 mg/L air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: based on the nasal histopathology data
- Key result
- Dose descriptor:
- NOEC
- Remarks:
- for reproductive parameters
- Effect level:
- 1 mg/L air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no treatment-related effects observed
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 0.16 other: mg/L
- System:
- respiratory system: upper respiratory tract
- Organ:
- nasal cavity
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- A slight but statistically significant decrease in viability index at birth (number of pups born alive per number of pups born) was observed in the 0.16 mg/L DBE group but this was considered to be unrelated to DBE exposure because it was not seen at either of the two higher exposure concentrations.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights at birth and weaning (21 days pp) were significantly lower in the 1.0 mg/L group. T
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- A slight decrease in relative kidney weight was seen in female pups whose parents were exposed to 0.40 mg/L of DBE; however, in the absence of a dose-response relationship, the decreased relative kidney weights were not considered to be related to DBE exposure. No differences were seen in the liver weights of DBE-exposed pups.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- All pups delivered by both DBE-exposed and control rats appeared outwardly normal.
- Histopathological findings:
- no effects observed
- Other effects:
- no effects observed
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Details on results (F1)
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- >= 1 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no treatment-related effects observed
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Reproduction parameters in rats exposed to DBE by inhalation
Parameter |
DBE Concentration [mg/L] |
|||
0 (control) |
0.16 |
0.40 |
1.0 |
|
Male fertility [%] |
12/20 60 |
16/20 80 |
15/20 75 |
18/20 90 |
Female fertility [%] |
17/20 85 |
17/20 85 |
17/20 85 |
20/20 100 |
Viability index at birth |
100 |
94.6 * |
99.6 |
99.0 |
Viability index day 0-4 |
99.5 |
93.7 |
99.2 |
98.2 |
Lactation index |
100 |
100 |
97 |
99 |
Gestation index |
100 |
100 |
100 |
100 |
Pups / litter [mean] |
13.1 |
12.5 |
12.6 |
12.9 |
Gestation duration [days] |
22.1 |
22.1 |
22.1 |
21.8 |
Pup weight at birth [g] |
6.4 (0.6) |
6.4 (0.8) |
6.1 (0.1) |
5.9 (0.1) * |
Pup weight at day 21 [g] Male Female |
44.3 (2.6) 41.0 (3.9) |
44.9 (4.3) 41.7 (4.7) |
45.5 (4.1) 44.3 (4.2) |
41.8 (2.8) * 40.8 (2.0) * |
* Significantly different to control, p < 0.05
Values in parentheses report standard deviation
Applicant's summary and conclusion
- Conclusions:
- Reproduction in rats was not altered by repeated inhalation exposure to up to 1.0 mg/L DBE, a concentration that produced both body weight and histologic effects in parental rats.
- Executive summary:
Dibasic Esters (DBE) has been tested in a reproduction toxicity study on Crl:CD(SD)BR rats after inhalation exposure using a protocol similar to OECD guideline no 415 and EU method B34 in compliance with US TSCA Good Laboratory Practice.
Groups of 20 male and 20 female rats were exposed to DBE at concentrations of 0 (control), 0.16, 0.40 (maximum attainable vapor), or 1.0 mg/L (aerosol) in whole-body inhalation chambers. Exposures were conducted for 6 hours/day, 5 days/week for 14 weeks (pre-breeding) then 7 days/week for 8 weeks (through breeding, gestation, and lactation). The exposures were interrupted for female rats between gestation day 19 and postpartum day 3. Parental examinations included clinical and cage side observations, body weight determination, and assessment of mating performance, fertility, gestation length, and lactation performance. The number and sex of pups, viability, and weight were determined. At the end of the lactation period, all parental rats and ten 21-day old pups of each sex were per group were killed and examined for gross abnormalities. Parental nose tissues were examined histopathologically.
No significant differences were observed between control and test rats with respect to mating performance, fertility, length of gestation, or progeny numbers, structure, and viability. Body weights of parental rats and of their offspring were reduced at 1.0 mg/L. The only histopathologic changes detected in the nasal tissues of the parental rats, was an exposure-related increase in squamous metaplasia in the olfactory epithelium. There was an increase in liver-to-body weight ratios in the two higher parental exposure groups and an increase in the lung-to-body weight ratio also seen at 1.0 mg/L. From the results obtained, it can be concluded that reproduction in rats was not altered by repeated inhalation exposure to up to 1.0 mg/L DBE, a concentration that produced both body weight and histologic effects in parental rats.
Dibasic Esters (DBE) is not classified for reproduction according to the criteria of Directive 67/548/EC and EU Regulation No. 1272/2008 (CLP).
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