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EC number: 231-609-1 | CAS number: 7651-02-7
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- other: 14 d dose range finding study
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2012-05-09 to 2012-05-30
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- 30 May 2008
- Deviations:
- no
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 03 October 2008
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- N-[3-(dimethylamino)propyl]stearamide
- EC Number:
- 231-609-1
- EC Name:
- N-[3-(dimethylamino)propyl]stearamide
- Cas Number:
- 7651-02-7
- Molecular formula:
- C23H48N2O
- IUPAC Name:
- N-[3-(dimethylamino)propyl]octadecanamide
- Test material form:
- solid: pellets
- Details on test material:
- - Name of test material: Stearic acid 3-(dimethylaminopropyl)amide
- Physical state: solid
- Analytical purity: not indicated, treated as 100%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: app. 6 weeks
- Housing: group housing of 3 animals per sex in Macrolon cages with sterilised sawdust as bedding material and paper as cage-enrichment
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24°C
- Humidity (%): 40-70%
- Air changes (per hr): 15/h
- Photoperiod (hrs dark / hrs light):12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
formulations were placed on a magnetic stirrer during dosing;
Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenised to a visually acceptable level. Adjustment was made for specific gravity of the vehicle.
Dose volume: 5 mL/kg bw, actual dose volumes were calculated weekly according to the latest body weight
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at testing laboratory and on information from the sponsor. - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- No chemical analysis of formulations were performed in the 14-day range finding study. Instead, analysis on formulations will be performed as part of the subsequent repeated dose toxicity study.
- Duration of treatment / exposure:
- 14 d
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50, 200, 500 mg/kg bw/d
Basis:
actual ingested
- No. of animals per sex per dose:
- 3
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Initially, one dose group at 500 mg/kg bw/d was initiated (next to a concurrent control group). Based on the results obtained at 500 mg/kg bw/d, two additional doses at 50 and 200 mg/kg bw/d were added one week later.
- Rationale for animal assignment (if not random): animals were allocated at random, with all animals within ± 20% of the sex mean
- Rationale for selecting satellite groups: no satellite groups were used in the dose range finding study
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily; animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily from start of treatment onwards, detailed clinical observations were made in all animals at 0-15 minutes, 1 hour (±15 minutes) and 3 hours (± 30 minutes) after dosing.
BODY WEIGHT: Yes
- Time schedule for examinations: Days 1, 4, 7, 10 and 14.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- over days 1-4, 4-7, 7-10 and 10-14
WATER CONSUMPTION: Yes
- 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: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table [No.1] were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
All animals at 500 mg/kg bw/d were sacrificed for humane reasons between Days 6 and 8.
No mortality occurred at 50 and 200 mg/kg bw/d.
500 mg/kg bw/d:
- lethargy, hunched posture, labored respiration, abdominal swelling, piloerection, chromodacryorrhoea, a lean appearance and/or ptosis from day 4 of treatment onwards
200 mg/kg bw/d:
- all animals showed piloerection on two days of week 2 only
50 mg/kg bw/d:
- no clinical signs were noted
Salivation seen after dosing among all animals at 200 and 500 mg/kg bw/d on a few days of treatment was considered to be a physiological response rather than a sign of systemic toxicity considering the nature and minor severity of the effect and its time of occurrence (i.e. after dosing).
BODY WEIGHT AND WEIGHT GAIN
500 mg/kg bw/d
- two females showed weight loss between days 1 and 4 (2 or 5% compared to day 1), followed by a slight weight gain between days 4 and 7. One female and all males at 500 mg/kg bw/d showed a reduced weight gain throughout the treatment period.
At 50 and 200 mg/kg, body weights and body weight gain remained in the same range as controls over the study period (the animals used for dosing at 50 and 200 mg/kg bw/d were from a different batch of delivery, and hence the starting body weight on day 1 was different to that for control animals and animals at 500 mg/kg bw/d).
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
500 mg/kg bw/d:
- food consumption before or after correction for body weight was reduced in both genders over days 1-4 and 4-7
200 mg/kg bw/d:
- food consumption before or after correction for body weight was similar to controls over the study period
50 mg/kg bw/d:
- food consumption before or after correction for body weight was similar to controls over the study period
HAEMATOLOGY
The following changes in haematology parameters distinguished treated from control animals and from normal range levels encountered for rats of this age and strain:
- Slightly lower red blood cell counts in males at 50 and 200 mg/kg bw/d (no clear dose related trend).
- Higher reticulocyte counts in males at 50 and 200 mg/kg bw/d (no clear dose related trend).
CLINICAL CHEMISTRY
The following changes in clinical biochemistry parameters distinguished treated animals from control animals and from normal range levels encountered for rats of this age and strain:
-higher alanine aminotransferase activity (ALAT) in two males at 50 mg/kg bw/d, and two males and one female at 200 mg/kg bw/d
-Higher alkaline phosphatase activity (ALP) in one female at 200 mg/kg bw/d
-Higher potassium level in males at 50 and 200 mg/kg bw/d
ORGAN WEIGHTS
Spleen and thymus weights of females at 200 mg/kg bw/d appeared slightly increased compared to the control group.
The apparent lower liver, spleen and heart weight of males at 200 mg/kg bw/d was ascribed to a slightly lower terminal body weight as the ratio to body weight for these organs was similar to control levels.
GROSS PATHOLOGY
500 mg/kg bw/d:
- reduced size of seminal vesicles, prostate, epididymides, spleen and/or thymus, gelatinous contents in the gastro-intestinal tract, small intestines and/or caecum, gastro-intestinal tract distended with gas, and emaciated appearance
200 mg/kg bw/d:
- no abnormalities
50 mg/kg bw/d:
- no abnormalities
HISTOPATHOLOGY: NON-NEOPLASTIC
500 mg/kg bw/d:
-Thymus: Lymphoid atrophy in 2/2 females (moderate).
-Stomach: Hyperplasia of the forestomach in 3/3 males and 3/3 females at slight or moderate degree, inflammation of the forestomach in 3/3 males and 3/3 females up to moderate degree, ulceration of the forestomach in 1/3 males and 1/3 females at slight degree.
-Duodenum: Hyperplasia of the villi in 2/3 males and 2/3 females up to slight degree.
-Jejunum: Hyperplasia of the villi in 1/3 females at minimal degree.
-Mesenterial lymph node: Foamy macrophages and sinusoidal dilation in 3/3 males and 3/3 females at slight or moderate degree, and congestion/erythrophagocytosis in 1/3 males and 2/3 females at minimal degree.
-Testes: Absence of spermiation (massive degree) and degeneration of spermatids in 3/3 males up to slight degree.
-Epididymides: Oligospermia in 2/2 males at massive degree and seminiferous cell debris in 2/2 males at slight degree.
-Prostate: Reduced contents in 2/2 males at slight degree.
-Seminal vesicles: Reduced contents in 2/2 males at moderate degree.
No treatment-related microscopic abnormalities were noted at 50 and 200 mg/kg bw/d.
Effect levels
- Dose descriptor:
- other: based on the results, doses were selected for OECD TG 421 study
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- not measured/tested
- Remarks:
- Effect level not specified (migrated information)
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
All animals at 500 mg/kg bw/d were sacrificed for humane reasons between Days 6 and 8, and showed lethargy, hunched posture, laboured respiration, abdominal swelling, piloerection, chromodacryorrhoea, a lean appearance and/or ptosis from Day 4 of treatment onwards. All animals showed weight loss or reduced body weight gain and reduced food consumption during the treatment period. Necropsy findings at 500 mg/kg bw/d primarily consisted of gelatinous contents in the gastro-intestinal tract or parts thereof, and emaciation. The main cause for moribundity at this dose level was forestomach ulceration and/or hyperplasia of the squamous epithelium of the forestomach. Other histopathological changes noted at this dose level included:
- Lymphoid atrophy of the thymus in 2/2 females examined, correlating to a reduced size of the thymus at necropsy.
- Hyperplasia and inflammation (3/3 males and 3/3 females) and ulceration (1/3 males and 1/3 females) of the forestomach.
- Hyperplasia of the villi in the duodenum (2/3 males and 2/3 females) and jejunum (1/3 females).
- Foamy macrophages and sinusoidal dilation (3/3 males and 3/3 females) and congestion/ erythrophagocytosis (1/3 males and 2/3 females) in the mesenterial lymph node.
- Absence of spermiation and degeneration of spermatids in the testes in 3/3 males, oligospermia and seminiferous cell debris in the epididymides, and reduced contents in the prostate and seminal vesicles in 2/2 males examined, which corresponded to a reduced size of seminal vesicles, prostate and epididymides at necropsy.
At 50 and 200 mg/kg bw/d, no mortality occurred. All animals at 200 mg/kg bw/d showed piloerection on two days of Week 2 only, whilst no clinical signs were noted at 50 mg/kgbw/d. Body weights, body weight gain and food intake remained in the same range as controls over the study period at these dose levels.
At 50 and 200 mg/kg bw/d, haematological changes consisted of slightly lower red blood cell and higher reticulocyte counts in males. No clear dose related trend was noted for these changes, which were generally slight in nature. Clinical biochemistry changes consisted of higher alanine aminotransferase activity in two males at 50 mg/kg bw/d, and two males and one female at 200 mg/kg bw/d, higher alkaline phosphatase activity in one female at 200 mg/kg bw/d, and higher potassium level in males at 50 and 200 mg/kg bw/d.
At 50 and 200 mg/kg bw/d, no abnormalities were noted at necropsy. Spleen and thymus weights of females at 200 mg/kg bw/d appeared slightly increased compared to the control group. No treatment-related histopathological changes were noted at 50 and 200 mg/kg bw/d.
Applicant's summary and conclusion
- Conclusions:
- In a 14 d dose range finding subacute toxicity study, Stearic acid 3-(dimethylaminopropyl)amide was administered to 3 Crl:WI(Han) rats/sex/dose orally via gavage at dose levels of 0, 50, 200 and 500 mg/kg bw/day.
All animals of the highest dose group were sacrificed for humane reasons based on clinical signs. The main cause for moribundity was forestomach ulceration and/or hyperplasia of the squamous epithelium of the forestomach.
In the 50 and 200 mg/kg bw/d dose groups, no mortality occurred, and no or only minor clinical signs were observed. No treatment related effects were observed at necropsy or histopathology. - Executive summary:
In a 14 d dose range finding study according to OECD guideline 407, adopted 03 October 2008, and EU method B.7, May 2008, Stearic acid 3-(dimethylaminopropyl)amide was administered to 3Crl:WI(Han) rats/sex/dose orally via gavage at dose levels of 0, 50, 200 and 500 mg/kg bw/day.
All animals in the 500 mg/kg bw/d dose group were sacrificed for humane reasons between days 6 and 8. They showed lethargy, hunched posture, laboured respiration, abdominal swelling, piloerection, chromodacryorrhoea, a lean appearance and/or ptosis from day 4 of treatment onwards. All animals showed weight loss or reduced body weight gain and reduced food consumption during the treatment period. Necropsy findings at 500 mg/kg bw/d primarily consisted of gelatinous contents in the gastro-intestinal tract or parts thereof, and emaciation. The main cause for moribundity at this dose level was forestomach ulceration and/or hyperplasia of the squamous epithelium of the forestomach. Other histopathological changes noted at this dose level included: lymphoid atrophy of the thymus, correlating to a reduced size of the thymus at necropsy; hyperplasia and inflammation of the forestomach; hyperplasia of the villi in the duodenum and jejunum; foamy macrophages and sinusoidal dilation and congestion/ erythrophagocytosis in the mesenterial lymph node; absence of spermiation and degeneration of spermatids in the testes, oligospermia and seminiferous cell debris in the epididymides, and reduced contents in the prostate and seminal vesicles, which corresponded to a reduced size of seminal vesicles, prostate and epididymides at necropsy.
At 50 and 200 mg/kg bw/d, no mortality occurred. All animals at 200 mg/kg bw/d showed piloerection on two days of week 2 only, whilst no clinical signs were noted at 50 mg/kg bw/d. Body weights, body weight gain and food intake remained in the same range as controls over the study period at these dose levels.
At 50 and 200 mg/kg bw/d, haematological changes consisted of slightly lower red blood cell and higher reticulocyte counts in males. No clear dose related trend was noted for these changes, which were generally slight in nature. Clinical biochemistry changes consisted of higher alanine aminotransferase activity in two males at 50 mg/kg bw/d, and two males and one female at 200 mg/kg bw/d, higher alkaline phosphatase activity in one female at 200 mg/kg bw/d, and higher potassium level in males at 50 and 200 mg/kg bw/d.
At 50 and 200 mg/kg bw/d, no abnormalities were noted at necropsy. Spleen and thymus weights of females at 200 mg/kg bw/d appeared slightly increased compared to the control group. No treatment-related histopathological changes were noted at 50 and 200 mg/kg bw/d.
Based on these results, dose leves were selected for the reproduction/developmental toxicity screening test according to OECD guideline.
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