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EC number: 271-865-1 | CAS number: 68610-44-6
- 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
Experimental in vivo study (Repeated Dose 28 -Day Oral Toxicity in Rodents, OECD 407) on the analogue substance " Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-ß-alaninate", CAS 94441 -92 -6 showing oral NOAEL over 28 days of 1000 mg/kg bw/day
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
- Study period:
- 18 May - 15 June 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: United States Environmental Protection Agency (EPA). Health Effects Test Guidelines, OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents. Office of Prevention, Pesticides and Toxic Substances (7101), EPA 712-C-00-366, July 2000.
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 6 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean (males: 159 grams; females: 133 grams).
- Housing: Group housing of 5 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle.
IN-LIFE DATES: From: 18 May - 14 June 2012 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 6 hours prior to dosing, and were homogenized to visually acceptable levels. Adjustment was made for density of the test substance. The dose concentrations were corrected for a test substance purity of 40.4%.
DOSE VOLUME: 5 ml/kg body weight. Actual dose volumes were calculated according to the latest body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were conducted on a single occasion treatment phase, according to a validated method (project 499169). Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 6 hours at room temperature was also determined (highest and lowest concentration). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration for solutions. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. Formulations were considered stable if the relative difference before and after storage was maximally 10%.
The purpose of this part of the study was to determine the accuracy of preparation, homogeneity and stability of the test substance in formulations.
For the formulation of Group 2, 3 and 4 prepared for use during treatment, the mean accuracy was outside the criterion of 90 – 110% of the target concentration (i.e. 86%, 76% and 89%). The mean accuracies were only slightly outside the criterion at the lowest (Group 2, i.e. 86%) and highest (Group 4, i.e. 89%) target concentration and were therefore considered acceptable. No test substance was detected in the Group 1 formulation. The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%). Formulations at the entire range were stable when stored at room temperature under normal laboratory light conditions for at least 6 hours. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily, 7 d/w.
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels were based on results of a 12-day dose range finding study with Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-ßalaninate (project 499174: Based on the results of the range finding study, dose levels suggested for the main study (28 days toxicity study) were: 50, 300 and 1000 mg/kg body weight. No clinical signs were observed. Therefore, clinical observations in the main study were conducted immediately after dosing.).
- Positive control:
- Not required.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS:
- Time schedule:At least twice daily. The time of death was recorded as precisely as possible.
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: At least once daily from start of treatment onwards, detailed clinical observations were made in all animals. Once prior to start of treatment and at weekly intervals, this was also performed outside the home cage in a standard arena. The time of onset, grade and duration of any observed signs were recorded. Signs were graded for severity.
BODY WEIGHT:
- Time schedule for examinations: Weekly.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data
WATER CONSUMPTION:
- Time schedule for examinations: Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
OPHTHALMOSCOPIC EXAMINATION: no
HAEMATOLOGY:
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: isoflurane
- Animals fasted: yes
- How many animals: all animals
- Parameters checked: According to test guidelines
CLINICAL CHEMISTRY:
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: isoflurane
- Animals fasted: yes
- How many animals: all animals
- Parameters checked: According to test guidelines
URINALYSIS: no
NEUROBEHAVIOURAL EXAMINATION:
- Time schedule for examinations: During week 4 of treatment
- Dose groups that were examined: all
- Battery of functions tested: hearing ability, pupillary reflex, static righting reflex and grip strength, motor activity test - Sacrifice and pathology:
- GROSS PATHOLOGY:
- All animals were fasted overnight with a maximum of 20 hours prior to planned necropsy, but water was provided. Animals surviving to scheduled necropsy and all moribund animals were deeply anaesthetised and subsequently exsanguinated.
- Dose groups that were examined: all groups
- Tissues/organs checked: According to test guidelines
ORGAN WEIGHTS:
Organs checked according to test guidelines
HISTOPATHOLOGY:
According to test guidelines - Statistics:
- - If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- The exact Fisher-test was applied to frequency data.
Motor activity data was subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences followed by the Wilcoxon test to compare the treated groups to the control group.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- Based on subjective appraisal.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- no evidence for dysfunction of organs
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- MORTALITY AND CLINICAL SIGNS
No mortality occurred during the study period that was considered to be related to treatment with the test substance. One male receiving 300 mg/kg died on scheduled day of necropsy between blood sampling and euthanasia. This was considered to be an accidental death and considered not to be related to treatment with the test substance. No clinical signs of toxicity were noted during the observation period. Salivation was incidentally noted in a single animal (on a single day). At the incidence observed, this finding was considered a sign of no toxicological significance.
BODY WEIGHT AND WEIGHT GAIN
Body weights and body weight gain of treated animals remained in the same range as controls over the study period.
FOOD CONSUMPTION AND FOOD EFFICIENCY
Food consumption before or after allowance for body weight was similar between treated and control animals.
HAEMATOLOGY
Haematological parameters of treated rats were considered not to have been affected by treatment. Statistically significant changes in platelet counts in females at 50 and 1000 mg/kg were considered to be of no toxicological significance as they occurred in the absence of a treatment-related distribution and remained within the range considered normal for rats of this age and strain.
CLINICAL CHEMISTRY
No toxicologically relevant changes occurred in clinical biochemistry parameters of treated rats. Statistically significant changes in creatinine level in males at 1000 mg/kg was considered to be of no toxicological significance as they remained within the range considered normal for rats of this age and strain and no corroborative effects were found at microscopic examination.
NEUROBEHAVIOUR
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals. The variation in motor activity did not indicate a relation with treatment.
ORGAN WEIGHTS
Thymus weight (absolute and relative to body weight) was found to be statistically higher in females at 1000 mg/kg compared to the control group. Other organ weights and organ to body weight ratios among the dose groups were similar to control levels.
GROSS PATHOLOGY
Necropsy did not reveal any toxicologically relevant alterations. The incidence of other incidental findings among control and treated animals was within the background range of findings that are encountered among rats of this age and strain. In addition these findings did not show a clear dose-related incidence trend. These necropsy findings were therefore considered to be of no toxicological relevance, and included diaphragmatic hernia, nodules in epididymides, fluid in the uterus, nodules in clitorial gland, foci in thymus and discolouration of the thymus.
HISTOPATHOLOGY
Minor, non-adverse, treatment-related microscopic findings were recorded in thymus of females and mesenteric lymph nodes of males:
Thymus: A slight increase in incidence of lymphocytolysis at a minimal degree was recorded in 4/5 females at 1000 mg/kg. This is a common background finding, which showed no clear dose-relation and was also recorded at minimal degree in 1/5 control females and 2/5 females at 50 mg/kg and was therefore not considered an adverse effect of the test item.
Mesenteric lymph nodes: Lymphoid hyperplasia was recorded at a minimal degree in some males of all Groups (Group 1: 1/5 males, Group 2: 1/5 males, Group 3: 2/5 males and Group 4: 3/5 males).
Lymphoid hyperplasia was also recorded in 1/5 females of Group 1 (control). The minimal lymphoid hyperplasia in the mesenteric lymph nodes and the remaining microscopic findings recorded were within the normal range of background pathology encountered in Wistar(Han) rats of this age and strain. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No toxicity was observed up to the highest dose level tested (NOAEL >= 1000 mg/kg)
- Key result
- Critical effects observed:
- no
- Conclusions:
- Based on the absence of functional or morphological disturbances supporting the changes noted for Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-ß-alaninate, a NOAEL of 1000 mg/kg was established.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across hypothesis is based on “different compounds which have similar properties”.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
- The source substance is identified as Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, also known as Sodium 3-[(2-carboxyethyl)(2-ethylhexyl)amino]propanoate (CAS no. 94441-92-6 | EC no. 305-318-6). It is a UVCB substance whose major constituent is sodium 2-ethylhexylimino-di-propionate. Minor constituents are sodium 2-ethylhexylimino-mono-propionate, unreacted acrylic acid and unreacted 2-ethylhexylamine.
- The target substance is identified as Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide (methanol free) (CAS no. 68610-44-6| EC no. 271-865-1). It is a UVCB substance whose major constituents are sodium 2-ethylhexylimino-mono-propionate and sodium 2-ethylhexylimino-di-propionate. Minor constituents are unreacted acrylic acid and unreacted 2-ethylhexylamine.
3. ANALOGUE APPROACH JUSTIFICATION
The target and source substances are essentially the same: both are UVCB substances composed of the exact same constituents with the exact same functional groups (i.e. carboxylic acid groups and secondary/tertiary amine groups). They are expected to have the same ADME profile and to share common mode of action and breakdown products. The target and source substances only differ in the overlapping ranges of their constituents, the content of sodium 2-ethylhexylimino-mono-propionate being especially higher in the target substance. This difference is expected to have no or very limited impact on the potency of effects exerted on exposed living organisms.
4. DATA MATRIX
Cf. read-across justification document attached in §13. Assessment reports. - Reason / purpose for cross-reference:
- read-across source
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No toxicity was observed up to the highest dose level tested (NOAEL >= 1000 mg/kg)
- Key result
- Critical effects observed:
- no
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- appropriate
Additional information
Justification for classification or non-classification
By analogy, the test item "2 -Propenoic acid, methyl ester, reaction products with 2-ethyl-1-hexanamine and sodium hydroxide (water and methanol free) is considered not to cause adverse effects.
Therefore it is not classified for repeated dose toxicity.
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