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Administrative data

Description of key information

OECD 423, oral rat: LD50cut-off 5000 mg/kg bw  (ATC method)
RA-S CAS 112-84-5, OECD 436, inhal. rat: LC50 >2.8 mg/L (ATC method), (highest feasible aerosol concentration with respirable MMAD)
RA-S CAS 112-84-5, OECD 402 dermal rat: LD50 >2000 mg/kg bw (limit test)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
1996
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Ltd, Margate, Kent, UK
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: males weighed 246-304g, and the females 194-215g
- Fasting period before study: overnight immediatly before dosing
- Housing: in groups of three by sex in solid-floor polypropylene cages furnished with woodflakes
- Diet: Rat and Mouse Expanded Diet No.1 (Special Diets Services Limited, Witham, Essex, UK) ad libitum
- Water: ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70%
- Air changes (per hr): 15/h
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

CLASS METHOD
- Rationale for the selection of the starting dose: According to Guideline OECD 423, Annex 2d
Doses:
Starting dose 2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity,1/2, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.
- Necropsy of survivors performed: yes, At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of an macroscopic abnormalities was recorded. No tissues were retained.
- Other examinations performed: clinical signs, body weight: Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment
Key result
Sex:
male/female
Dose descriptor:
LD50 cut-off
Effect level:
5 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occured.
Clinical signs:
other: No signs of systemic toxicity were noted during the study.
Body weight:
other body weight observations
Remarks:
All animals showed expected gains in bodyweight during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
other: CLP criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate, reliable (Klimisch score 1) and consistent study. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-conducted study conducted under GLP with no deviations. Reliability was changed from "1" to "2" according to the ECHA guidance document "Practical guide 6: How to report read-across and categories".
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Conditions: Animals were housed in an Optimal Hygienic Conditions (OHC) inside a barrier system. Air-conditioned with 10 - 15 air changes per hour, continuously monitored environment with a temperature range of 22 ± 3 °C, a relative humidity range of 30 - 70% and a 12 hour fluorescent light / 12 hour dark cycle. A radio program was played during most of the light period.

Accommodation: Animals were housed in groups of 5 of the same sex in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding ("Lignocel" J. Rettenmaier & Söhne GmbH & Co KG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) including paper enrichment (Enviro-dri from Lillico, Biotechnology, Surrey, UK).

Diet: Animals had ad libitum access to a pelleted standard Harlan Teklad 2914C rat maintenance diet (Provimi Kliba AG, 4303 Kaiseraugst, Switzerland) batch no. 82/09 except during the period when the animals were restrained in exposure tubes. Results of the analyses for contaminants and their limits of acceptability are archived at Harlan Laboratories Ltd.

Water: Community tap water from Füllinsdorf ad libitum in water bottles, except during the period when they were restrained in exposure tubes. Results of representative analyses for contaminants are archived at Harlan Laboratories Ltd.
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
Method of test material administration: Inhalation by nose-only, flow-past exposure.
Rationale for Method: Inhalation is a possible route of human exposure.
Frequency of Administration: Single, 4-hour exposure period. Exposure was interrupted twice for a total of 2 minutes for cleaning; nevertheless, the animals were exposed for a period of 4 hours as those interruptions were accounted for.

Rationale for Aerosol Concentration: The target concentration of 3 mg/L air for 4 hours was the highest feasible aerosol concentration with a respirable MMAD as determined during the technical trials.

Duration of Observation Period: 14 days
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric determination
Duration of exposure:
4 h
Concentrations:
2.8 mg/l
No. of animals per sex per dose:
five
Control animals:
no
Details on study design:
Inhalation exposure was performed using a flow-past, nose-only exposure system. The animals were confined separately in restraint tubes which were positioned radially around the exposure chamber. The exposure system ensured a uniform distribution and provided a constant flow of test material to each exposure tube. The flow of air at each tube was 1.0 L/min, which is sufficient to minimize re-breathing of the test aerosol as it is more than twice the respiratory minute volume of rodents. Before commencement of the exposure of the group, technical trials were conducted (without animals) using the inhalation system foreseen for the study. The technical trials were conducted using established procedures based on GLP, but were not
inspected by the Harlan Laboratories Ltd. Quality Assurance. Technical trial data are retained in the raw data.

A group of three male and three female albino rats [RccHanTM:WIST(SPF)] was exposed by nose-only, flow-past inhalation for four hours to the test item at a gravimetrically determined mean concentration of 2.8 mg/L air. All animals were observed for clinical signs and mortality during the inhalation exposure and the subsequent 14-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 2, 4, 8 and 15 before necropsy. On test day 15 all animals were sacrificed and necropsied. The ranges of aerosol concentration, temperature, relative humidity, oxygen content and airflow rate measured during the exposure were considered to be satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats.
Statistics:
None
Preliminary study:
The LC50 of erucamide in this study was estimated to be greater than 2.8 mg/L air (gravimetrically determined mean aerosol concentration) which was the highest feasible aerosol concentration with a respirable MMAD.
Key result
Sex:
male/female
Dose descriptor:
LC0
Effect level:
2.8 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Highest feasible aerosol concentration with a respirable MMAD.
Mortality:
All animals survived the scheduled observation period.
Clinical signs:
other: Ruffled fur was recorded in all animals one hour after the end of exposure. There were no clinical signs from test day 2 onwards.
Body weight:
From test day 1 to test day 2, slight body weight loss was noted in all animals. Thereafter normal body weight development was recorded.
Gross pathology:
There were no macroscopic findings.
Other findings:
None

Temperature, relative humidity and oxygen concentration during exposure were considered to be satisfactory for this type of study. Relative humidity values were low as dry air was used for aerosol generation. The mean gravimetric aerosol concentration determined was 2.8 mg/L air as targeted. The aerosol concentration was stable during the exposure period. The Mass Median Aerodynamic Diameters (MMAD) obtained from three gravimetric measurements of particle size distribution during the exposure were similar (MMAD = 3.02 μm, 3.51 μm and 3.84 μm). This led to the conclusion that the particle size of the generated aerosol was fairly stable during the whole exposure period. The MMADs were within the target range of 1 to 4 μm or at the upper limit (third sample), thus deposition of the particles can be assumed to have occurred in both the upper and the lower respiratory tract. The aerosol concentration was at the technical limit as the third sample was at the upper limit. In addition, the Geometric Standard Deviations (GSD) were within the target range of 1.5 to 3. Hence, the particle size distributions obtained were considered to be appropriate for acute inhalation toxicity testing.

Interpretation of results:
other: CLP criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
In conclusion, the LC50 of (Z)-docos-13-enamide obtained in this study was estimated to be greater than 2.8 mg/L air (gravimetrically determined mean aerosol concentration) which was the highest feasible aerosol concentration with a respirable MMAD.
Executive summary:

A group of three male and three female albino rats [RccHanTM:WIST(SPF)] was exposed by nose-only, flow-past inhalation for four hours to the test item at a gravimetrically determined mean concentration of 2.8 mg/L air. All animals were observed for clinical signs and mortality during the inhalation exposure and the subsequent 14-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 2, 4, 8 and 15 before necropsy. On test day 15 all animals were sacrificed and necropsied. The ranges of aerosol concentration, temperature, relative humidity, oxygen content and airflow rate measured during the exposure were considered to be satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats. All animals survived the scheduled observation period. Ruffled fur was recorded in all animals one hour after the end of exposure. There were no clinical signs from day 2 onwards. There were slight effects on body weight. There were no macroscopic findings. In conclusion, the LC50 of (Z)-docos-13-enamide obtained in this study was estimated to be greater than 2.8 mg/L air (gravimetrically determined mean aerosol concentration) which was the highest feasible aerosol concentration with a respirable MMAD.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
> 2.8 mg/L air
Physical form:
inhalation: dust
Quality of whole database:
GLP guideline study with a structurally related substance according to the criteria of Regulation (EC) No 1907/2006. Annex XI, paragraph 1.5. Reliability of study originally Klimisch 1, but reliability was changed to "2" according to the ECHA guidance document "Practical guide 6: How to report read-across and categories".

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-conducted study performed under GLP with certificate. Reliability was changed from "1" to "2" according to the ECHA guidance document "Practical guide 6: How to report read-across and categories".
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animals were housed under standard laboratory conditions. Rooms were air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 ± 3 °C and for relative humidity between 30-70% (values above 70% during cleaning process were possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.

Accommodation: During acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with standard softwood bedding (‘Lignocel’ J. Rettenmaier & Söhne GmbH & Co. KG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) during treatment and observation.

Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 58/09 (Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) ad libitum.
Results of respective analyses for contaminants are included in the study report.
Water: Community tap water from Itingen was available ad libitum. Results of bacteriological assay, chemical and contaminant analyses of respective samples are included in the study report.
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
One day before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10% of the total body surface. Only those animals without injury or irritation on the skin were used in the test.

On test day 1, the test item was applied at a dose of 2000 mg/kg body weight evenly to a moistened surgical gauze pad (ca. 5 x 5 cm), placed on the exposed site and held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and an elastic adhesive restrainer bandage wrapped around the abdomen. The test item will remain in contact with the skin for 24 hours. Twenty-four hours after the application the dressing was removed and the skin was flushed with lukewarm tap water and dried off with disposable paper towels. Thereafter, the exposure sites
were assessed.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
not required
Details on study design:
Viability / Mortality: Daily during the acclimatization period, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with clinical signs) and twice daily during days 2 - 15.
Clinical Signs: Daily during the acclimatization period, within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1, then once daily during days 2 - 15.
Local Dermal Signs: Once daily during days 2 (following dressing removal) through day 15 using the numerical scoring system described elsewhere in the study report.
Body Weights: On test days 1 (prior to administration), 8 and 15.
Statistics:
None
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: limit test
Mortality:
No deaths occurred during the study.
Clinical signs:
other: No clinical signs were evident during the course of the study.
Body weight:
other body weight observations
Remarks:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopical changes were evident at necropsy.
Other findings:
Slight desquamation was noted in one male on the observation days 7 and 8.
No dermal changes were seen in the females.
Interpretation of results:
other: CLP criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
The acute dermal LD50 of erucamide (112-84-5) in rats is >2000 mg/kg bw.
Executive summary:

Five male and five female RccHan:WIST (SPF) rats were treated with erucamide at 2000 mg/kg by dermal application. The test item was applied to a gauze patch moistened with water. The application period was 24 hours. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2 - 15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. No deaths occurred during the study. No clinical signs were evident during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. Slight desquamation was noted on day 7 - 8 of observation in a single male. All other animals were without findings. No macroscopical findings were evident. The median lethal dose of erucamide after single dermal administration to rats of both sexes, observed over a period of 14 days, is: LD50 (rat): greater than 2000 mg/kg body weight

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
> 2 000 mg/kg bw
Quality of whole database:
GLP guideline study with a structurally related substance according to the criteria of Regulation (EC) No 1907/2006. Annex XI, paragraph 1.5. Reliability of study originally Klimisch 1, but reliability was changed to "2" according to the ECHA guidance document "Practical guide 6: How to report read-across and categories".

Additional information

There is data available from an acute oral toxicity study following OECD Guideline 423 (Acute Toxic Class Method) in form of a limit test with Amides, C16-C18 (even numbered) (Sanders, 2000). A starting dose of 2000 mg/kg bw was subsequently applied to 3 animals of each sex. No mortality occurred either in the females or in the males, no signs of systemic toxicity were observed, and the animals showed the expected gain in bodyweight during the study. Therefore, according to the scheme outlined in Annex 2d of OECD guideline 423 the LD50 cut-off value for acute oral toxicity was determined to be 5000 mg/kg bw.

No test data for Amides, C16-C18 (even numbered) is available for acute dermal and acute inhalation toxicity testing. Therefore, a read-across from a structurally related substance, erucamide (CAS 112-84-5), is included for regulatory purposes. Erucamide is the fatty acid amide resulting from the amidation of erucic acid. Erucic acid is a mono-unsaturated fatty acid with a carbon chain consisting of 22 carbon atoms with a double bond at position 13 (omega-9) of the carbon chain (cis-docos-13-enoic acid). Comparable to Amides, C16-C18 (even numbered) it is not classified in Annex I of Directive 67/548/EEC, and does not have to be self-classified according to the available experimental data. Erucic acid is also present in various oils and fats which are part of our diets (20-40% in oils from mustard seeds and up to 50% in original high erucic acid rapeseed oil, <2% in low erucic acid rapeseed oil; Beare-Rogers, 2001) and will also be broken down into shorter-chain fatty acids in the process of beta-oxidation. One of the most famoust uses is in Lorenzo's oil, a 4:1 mixture of the triglyceride forms of oleic and erucic acid, i.e. an investigational drug used for the treatment of adrenoleukodystrophy, for which an U.S. Patent was established. Testing of erucamide for acute oral toxicity following OECD guideline 423 as limit test with a starting dose of 2000 mg/kg bw, performed by the same testing facility as for Amides, C16-C18 (even numbered), revealed comparable results to Amides, C16-C18 (even numbered): no mortality occurred, no signs of systemic toxicity were observed, and animals showed the expected gains in bodyweight.

Therefore, both substances are considered to have comparable toxicological characteristics. Considering animal welfare reasons, a read-across from the tests for acute inhalation and dermal toxicity conducted with erucamide (CAS 112-84-5) is reasonable and justified.

The acute inhalation toxicity test was performed according to OECD Guideline 436 (Acute Toxic Class Method) with the maximum attainable aerosol concentration of erucamide still ensuring particles with a respirable MMAD as recommended in the guideline (Pothman, 2010). In the study the animals were nose-only exposed for 4 hours to an aerosol with MMADs ranging from 3.02 to 3.84 µm and a concentration of 2.8 mg/L. No mortality occurred, and the only effects observed during the 14-day observation period were ruffled fur one hour after the end of exposure and slight body weight loss from day 1 to day 2. No effects were observed from day 2 onwards. Therefore, the LC50 was established to be >2.8 mg/L for a 4-hour exposure period. According to OECD Guideline 436, Annex 5d for Acute Inhalation Toxicity testing with a starting concentration of 5 mg/L/4h for dusts and mists, the LC50 cut-off for acute inhalation toxicity can even be defined as "∞", as the starting dose already represented the maximum technically attainable concentration, and under handling conditions no higher concentration of a comparable respirable size will occur.

The acute dermal toxicity study with erucamide, designed as limit test, was performed according to OECD Guideline 402 (Braun, 2010). Five rats per sex were exposed for 24 hours to a dose of 2000 mg/kg bw under semicocclusive conditions. After exposure the treated skin sites were cleaned with lukewarm water and the dermal reactions were assessed. During the 14-day observation period no mortality occurred; no signs of systemic toxicity were observed, and the animals showed the expected gains of body weight. Local observations at the exposure site in form of slight desquamation were made in one male on observation days 7 and 8; no dermal effects were observed in the females. Therefore, the LD50 for acute dermal toxicity was determined to be >2000 mg/kg bw.

Justification for classification or non-classification

Based on the results for the test substance itself and the results obtained from the structurally related substance erucamide, Amides C16-C18 (even numbered) does not have to be classified for acute toxicity according to the criteria of Regulation (EC) No 1272/2008.