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EC number: 203-828-2 | CAS number: 111-05-7
- 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
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- 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
Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013-01-14 to 2013-03-14
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- N-(2-hydroxypropyl)oleamide
- EC Number:
- 203-828-2
- EC Name:
- N-(2-hydroxypropyl)oleamide
- Cas Number:
- 111-05-7
- Molecular formula:
- C21H41NO2
- IUPAC Name:
- N-(2-hydroxypropyl)oleamide
- Details on test material:
- - Name of test material (as cited in study report): N-(2-hydroxypropyl)Oleamide
- Substance type: chemical
- Physical state: beige waxy solid
- Analytical purity: 100 % dry matter
- Lot/batch No.: T22221 without solvent
- Expiration date of the lot/batch: 29/05/2014 (retest date)
- Stability under test conditions: unknown
- Storage condition of test material: at room temperature
Constituent 1
Method
- Target gene:
- Histidine
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Metabolic activation:
- with and without
- Metabolic activation system:
- Rat Liver Microsomal fraction S9-mix
- Test concentrations with justification for top dose:
- In the bacteriostatic assay : 5000 - 1500 - 500 - 150 - 50 µg/plate
In the 1st mutagenic assay :
- without metabolic activation :
5000 - 1500 - 500 - 150 - 50 µg/plate in strains TA1535, TA1537 and TA98
5000 - 1500 - 500 - 150 - 50 - 15 µg/plate in strain TA100
5000 - 1500 - 500 - 150 - 50 - 15 - 5 µg/plate in strain TA102
- with metabolic activation :
500 - 150 - 50 - 15 - 5 - 1.5 µg/plate in strain TA1535
5000 - 1500 - 500 - 150 - 50 - 15 µg/plate in strain TA100
5000 - 1500 - 500 - 150 - 50 - 15 - 5 µg/plate in strain TA102 - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: ethanol
- Justification for choice of solvent/vehicle: As indicated by the Sponsor and specified in the Final Study Plan, the test item N-(2-hydroxypropyl)Oleamide was dissolved in ethanol.
As indicated by the Sponsor and specified in the Final Study Plan, the test item N-(2-hydroxypropyl)Oleamide was dissolved in ethanol (Merck, batches K43508483225 for the bacteriostatic and the 1st mutagenic assays and K42909883148 for the 2nd, 3rd and 4th assays).
The test item was soluble at a maximum concentration of 679.12 mg/mL in ethanol.
For the bacteriostatic assay, it was dissolved at the maximal initial concentration of 50 mg/mL in order to obtain the top dose of 5000 µg/plate when added at 100 µL/plate. Nevertheless, an unexpected toxicity with no dose-effect relationship, in particular in the negative control was observed at the microscopic examination of the background growth. It was thus decided in accordance with Amendment No. 1 to FSP-IPL 121202 to perform another toxicity assay with a volume of treatment decreased down to 50 µL/plate.
For the 2nd bacteriostatic assay and the 1st and the 2nd mutagenic assays, the test item was thus dissolved at a higher initial concentration of 100 mg/mL in order to obtain the top dose of 5000 µg/plate when added at 50 µL/plate.
Finally for the 3rd and the 4th mutagenic assays, the test item was dissolved at the maximal initial concentration of 30 mg/mL in order to obtain the top dose of 1500 µg/plate when added at 50 µL/plate (without S9-mix) or at a maximal initial concentration of 200 mg/mL to obtain the top dose of 5000 µg/plate when added at 25 µL/plate (with S9-mix, with pre-incubation).
The limiting factor for maximum dose in the toxicity assay was thus maximum dose according to OECD Guideline.
Successive dilutions were also prepared with ethanol and used at either 100 or 50 or 25 µL/plate.
The stability of the test item in the solvent was unknown but preparations for treatment were performed just before use.
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- Ethanol
- Positive controls:
- yes
- Remarks:
- - Without S9-mix: sodium azide (TA1535, TA100) 9-amino-acridine (TA1537) 2-nitro fluorene (TA98) mitomycin C (TA102) - With S9-mix: 2-anthramine (TA1535, TA1537, TA98, TA100) benzo[a]pyrene (TA102)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation) and preincubation (only for the 3rd and 4th assays with metabolic activation)
DURATION
- Preincubation period: 60 min
- Exposure duration: 48 h
- Expression time (cells in growth medium): not applicable
- Selection time (if incubation with a selection agent): not applicable
- Fixation time (start of exposure up to fixation or harvest of cells): not applicable
SELECTION AGENT (mutation assays): histidine withdrawal
SPINDLE INHIBITOR (cytogenetic assays):
STAIN (for cytogenetic assays):
NUMBER OF REPLICATIONS: triplicate for each dose and positive control, 6 replicates for negative control
NUMBER OF CELLS EVALUATED: not applicable
DETERMINATION OF TOXICITY
- Method: microscopic observation of the background growth - Evaluation criteria:
- Criteria based on biological significance
A test item causing a positive response proportional to the dose for at least 3 doses with, for the highest increase, a value greater than or equal to 3 times (for strains TA1535, TA1537) or 2 times ( for strains TA98, TA100, TA102) the value for the solvent control, is considered positive in the assay.
Criteria based on statistical significance
see below
Reproducibility
If a test item causes a positive response during a single assay and that result cannot be reproduced in at least 1 independent assay, the initial positive result may be considered as not significant.
Comparison to historical control data
In some borderline cases, an additional criterion to be considered is the comparison between the number of revertants induced by the test item and the laboratory historical control data. Indeed, an increase in each individual value that is above the highest value of corresponding historical control data can help supporting a conclusion such as “equivocal” or “weak” mutagen. - Statistics:
- In parallel, data will be analysed by means of Dunnett's method (Mahon et al, 1989) allowing the comparison of the mean value for each dose to the mean value for the corresponding solvent control.
Results and discussion
Test results
- Species / strain:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: not applicable
- Effects of osmolality: not applicable
- Evaporation from medium: not applicable
- Water solubility: unknown
- Precipitation:
In the first toxicity assay (Table 1), slight and moderate precipitates were observed in all strains both with and without metabolic activation at the 2 highest doses tested of 1500 and 5000 µg/plate, respectively. However, it is noteworthy that due to unexpected toxicity, a 2nd assay was performed.
In the 2nd toxicity assay (Table 1-continued), precipitates were observed as described below :
-strong precipitate in strain TA1537 without metabolic activation at the highest dose tested of 5000 µg/plate.
-moderate precipitates at the 2 highest doses tested of 1500 and 5000 µg/plate in strains TA1535, TA98 and TA102 both with and without metabolic activation and in strain TA100 without metabolic activation; at the highest dose of 5000 µg/plate in strains TA1537 and TA100 with metabolic activation; at the 2 doses of 1500 and 500 µg/plate in strain TA1537 without metabolic activation.
-slight precipitates at the 2 doses of 1500 and 500 µg/plate in strain TA1537 with metabolic activation; at the dose of 1500 µg/plate in strain TA100 with metabolic activation; at the 2 doses of 500 and 150 µg/plate in strain TA98 both with and without metabolic activation and in strain TA102 with metabolic activation; at the dose of 500 µg/plate in strain TA1535 both with and without metabolic activation and in strains TA100 and TA102 without metabolic activation; at the dose of 150 µg/plate in strain TA1537 without metabolic activation.
In the 4 mutagenicity assays, some slight to moderate precipitates were found again at the 1 to 3 highest doses tested.
- Other confounding effects:
RANGE-FINDING/SCREENING STUDIES:
In the first toxicity assay (Table 1), slight to potent toxicity was observed in all strains both with and without metabolic activation but especially without metabolic activation and up to the 5 doses tested. Moreover, an unexpected toxicity was observed in the negative control with a decrease in the frequencies of spontaneous revertants. This toxicity could thus be due to the intrinsic toxicity of ethanol at high dose volume (100µL/plate). It was thus decided in accordance with the Amendment No. 1 to FSP-IPL 121202 to perform another toxicity assay with a volume of treatment decreased down to 50 µL/plate.
In the 2nd toxicity assay, toxicity was observed as described below :
-strong toxicity at the 2 highest doses tested of 1500 and 5000 µg/plate in strains TA1535, TA1537, TA100 and TA102 without metabolic activation.
-moderate toxicity at the highest dose tested of 5000 µg/plate in strain TA98 without metabolic activation and in strains TA1537 and TA98 with metabolic activation; at the 3 highest doses tested from 500 to 5000 µg/plate in strain TA100 and TA102 with metabolic activation; at the 2 doses of 150 and 500 µg/plate in strain TA1537, TA100 and TA102 without metabolic activation; at 500 µg/plate in strain TA1535 without metabolic activation.
-slight toxicity at the 2 doses of 1500 and 5000 µg/plate in strain TA1535 with metabolic activation; at the 3 doses from 150 to 1500 µg/plate in strain TA98 without metabolic activation; at the 4 doses from 50 to 1500 µg/plate in strains TA1537 and TA98 with metabolic activation but this toxicity was also observed in negative control; at the 2 doses of 50 and 150 µg/plate in strains TA100 and TA102 with metabolic activation; at 150 µg/plate in TA1535 without metabolic activation and at 50 µg/plate in strains TA1537, TA100 and TA102 without metabolic activation.
COMPARISON WITH HISTORICAL CONTROL DATA:
Concurrently to the main assays, tests were carried out on reference mutagenic test compounds in order to show the sensitivity of the strains tested and the efficiency of the metabolic activation system. Statistically and biologically significant increases in the numbers of revertants were observed in the presence of positive reference test substances. The values observed were within the limits of historical controls with some minor exceptions (See Below). The frequencies of spontaneous revertants (solvent controls) were within the limits generally observed under our experimental conditions with a minor exception. The frequencies of spontaneous revertants (solvent controls) in the 3rd assay in strain TA102 with metabolic activation with preincubation was below the lower limit generally observed under our experimental conditions (i.e. 159.0 vs. 200 – 568). Nevertheless, this deviation was considered as minor. It did not affect the quality or the integrity of the study data and did not impair the conclusion of the study.
The validity criteria for the test were fulfilled. - Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
Any other information on results incl. tables
The search for any mutagenic activity ofN-(2-hydroxypropyl)Oleamide(Batch T22221 without solvent) provided by SEPPIC, was studied by means of the Ames’ test (Salmonella his-/microsome system) in compliance with the Commission Regulation EC 440/2008 and the OECD Guideline 471 using the highest dose compatible with the toxic activity. Four to seven lower dilutions were also tested.
The summaries of the test results are given in Appendix No. 1 (Tables 2, 3, 4 and 5). The individual results for mutagenicity assays are shown in Appendix No. 2 (Tables 7 to 22).
In the third assay in strain TA98 in presence of metabolic activation(Table 19), a statistically significant increase was observed at the intermediary dose tested of 50 µg/plate with an induction ratio of 1.9,i.e.below the threshold ratio for a biologically significant response (set at 2 in this strain). No dose-response relationship was observed and the value for the mean number of revertants was within the range of values for negative control in historical data (i.e.11 – 57).
The N-(2-hydroxypropyl)Oleamide is not mutagenic in this condition.
In strain TA102 in absence of metabolic activation(Table 11), statistically significant increases in the number of revertants were noted at the 2 intermediary doses of 5 and 15 µg/plate with induction ratios of 1.9. The threshold ratio for a biologically significant response (set at 2 in this strain) was thus not reached, no dose-response relationship was observed and the value for the mean number of revertants was within the values for negative control in historical data (i.e.48 – 354) Furthermore, the second and the third assay were clearly negative, with neither statistically nor biologically significant increase in the number of revertants (Tables 16 and 21).
The N-(2-hydroxypropyl)Oleamide is not mutagenic in this condition.
In the third assay in strain TA102 in presence of metabolic activation(Table 21), statistically significant increases in the number of revertants were noted at the 4 intermediary doses from 50 to 1500 µg/plate with induction ratios from 1.5 to 1.9. The threshold ratio for a biologically significant response (set at 2 in this strain) was thus not reached and the values for the mean number of revertants was within the values for negative control in historical data (i.e.200 – 568). The statistically significant assay was certainly due to the low level ofspontaneous revertants but a dose-response relationship was observed up to the dose of 500 µg/plate. It was thus decided to reiterate the assay in this specific condition.
In the fourth assay in strain TA102 in presence of metabolic activation(Table 22), neither statistically nor biologically significant increase in the number of revertants was noted at all the doses tested.
The N-(2 -hydroxypropyl)Oleamide is not mutagenic in this condition.
Except the meaningless increases mentioned above, in three independent assays performed either with or without metabolic activation (the third assay with S9-mix was performed according to the pre-incubation protocol), no biologically significant increase in the mean number of revertants was noted in the five Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA102 tested, in the presence of N-(2-hydroxypropyl)Oleamide.
Furthermore, some statistically significant decreases in the mean number of revertants were observed. Nevertheless, these effects were probably due to the toxic activity of the test item and had no meaning in terms of mutagenic hazard.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
negative
The mutagenic activity of the test item N-(2-hydroxypropyl)Oleamide (Batch T22221 without solvent) provided by SEPPIC was assessed by means of the Ames’s test in the five Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA102 tested either in presence or in absence of metabolic activation, in three or four independent assays.
The validity criteria for the assay were fulfilled. The study was thus considered as valid.
Under these experimental conditions, no mutagenic activity was revealed. - Executive summary:
Bacterial Reverse Mutation Test
On five strains of Salmonella typhimurium His-using B.N. AMES' Technique
SUMMARY
TEST ITEM : N-(2-hydroxypropyl)Oleamide
BATCH NUMBER : T22221 without solvent
STUDY LOCATION : INSTITUT PASTEUR DE LILLE
Genetic Toxicology Laboratory
1, rue du Professeur Calmette - B.P. 245
59019 LILLE CEDEX FRANCE
THIS STUDY WAS CARRIED OUT IN COMPLIANCE WITH GOOD LABORATORY PRACTICE REGULATIONS
Study initiation date (date Study Director signed Study Plan): 14/01/2013
Experimental start date: 14/01/2013
Experimental completion date: 14/03/2013
AIM
The search for any mutagenic activity ofN-(2-hydroxypropyl)Oleamide(BatchT22221 without solvent) studied by means of the Ames’ test (Salmonella his-/microsome system) in compliance with the Commission Regulation EC 440/2008 and the OECD Guideline 471.
METHODS
Strains used : TA1535, TA1537, TA98, TA100, TA102
Solvent : ethanol (Merck, Batches K43508483225 and K42909883148)
Stability in the solvent : unknown (dilutions were prepared extemporaneously)
TOXICITY ASSAYS
Preliminary test of toxic activity : carried out on 5 strains – Incubation period: 48 h
Sterility test : absence of contamination
Limiting factor for maximum dose : maximum dose according to OECD Guideline
Doses used in toxicity assay :expressed asµg/plateN-(2-hydroxypropyl)Oleamide
Volumes of treatment : 1stassay: 100 µL/plate as specified in the Final Study Plan
2ndassay 50 µL/plate as specified in the Amendment No. 1
1stassay(under 100 µL/plate):
The examination of the background growth demonstrated unexpected toxicity in the negative control. This could be due to the intrinsic toxicity of ethanol at high dose volume of 100 µL/plate. It was this decided in accordance with Amendment No. 1 to FSP-IPL 121202 to perform another toxicity assay with a volume of treatment decreased down to 50 µL/plate.
2ndassay(under 50 µL/plate):
The examination of the background growth demonstrated thatN-(2-hydroxypropyl)Oleamideinduced slight to strong toxicity in all strains depending on the condition or the dose tested. Moreover, slight to important precipitates in all strains were observed.
Therefore, the maximum doses retained for the first mutagenicity assay were:
- Without metabolic activation:
o In strains TA1535, TA1537, TA98 and TA102: 500 µg/plate
o In strain TA100: 250 µg/plate
- With metabolic activation: 5000 µg/plate in all strains.
The dose volume was set at 50 µL/plate.
MUTAGENICITY ASSAYS
Mutagenicity test : carried out on 5 strains both with and without metabolic activation using hepatic microsomes from rat livers induced by Aroclor 1254 – Incubation period: 48h
Number of assays : 2 or 3 (the last assay with metabolic activation was performed according to the pre-incubation method) or 4 (only in strain TA102 with metabolic activation, the 2 last assays were performed according to the pre-incubation method)
Limiting factor for maximum dose : maximum dose according to OECD Guideline or toxic activity (depending on the strains and/or the experimental conditions)
Doses used in main test :expressed asµg/plate pureN-(2-hydroxypropyl)Oleamide
Volume of treatment : 50 µL/plate as specified in the Amendment No. 1 to FSP-IPL 121202
Results:
In the 1st assay, no biologically significant increase in the mean number of revertants was observed. However, a too strong toxicity (that could be due to the batch of solvent) and invalidated positive controls were noted. When gathering these observations, in order to bring confident conclusions, it was decided to reiterate the assay in all the conditions even in the ones that were not invalidated.
In the 3rd assay, no biologically significant increase in the mean number of revertants was observed.
In the 4th assay (performed only in strain TA102 in presence of metabolic activation), no biologically significant increase in the mean number of revertants was observed.
CONCLUSION
The mutagenic activity of the test item N-(2-hydroxypropyl)Oleamide (Batch T22221 without solvent) was assessed by means of the Ames’s test in the five Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA102 tested either in presence or in absence of metabolic activation, in three or four independent assays.
The validity criteria for the assay were fulfilled. The study was thus considered as valid.
Under these experimental conditions, no mutagenic activity was revealed.
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