N-octyldecyloctadecanamide

Endpoint summary

Description of key information

The oral route was deemed as the most appropriate route of exposure considering the properties and uses of the substance.

A subchronic repeated dose toxicity study conducted on a suitable analogue returned a NOAEL of 1000 mg/kg bw/d.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 6th of August to 5th of November, 2013

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 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

other: Wistar, derived SPF- Albino, Crt: Wi/Br

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Versuchstierzucht, Charles River Wiga, 8741 Sulzfeld
- Age at study initiation: about 5 weeks (born the 1st and 2st July, 1987)
- Weight at study initiation: Males from 129 g to 170 g; Females from 115 g to 138 g
- Date of receipt: July 30th, 1987
- Animal health: at the entrance, at the test initiation. Certification available.
- Housing: in makrolon R cages.
- Bedding: "Altromin Laboreinstreu" of pure soft wood, dried, disdusted and sterilized at 180°C, supplied by Altromin GmbH, 4937 Lage, renewed weekly.
- Diet: Ssniff R pelletted diet (standard laboratory rat diet), ad libitum
- Diet quality assurance: diet analysed periodically from chlorinated hydrocarbons, aflatoxins, heavy metals, arsenic, and antibiotic activity (by "Landwirtschaf tliche Untersuchungs' und Forschungsanstalt - Kiel" (LUFA, independent laboratory). Certification avalaible.
- Water: tap water from Makrolon R drinking bottles, ad libitum
- Water quality assurance: water was collected twice yearly and analysed from analyses for chlorinated hydrocarbons, heavy metals and arsenic according to "Trinkwasserverordnung" by a governmental chemical institute for chemical quality. Water was controlled bacteriologically by governmental institute for public health. Certification available.
- Acclimation period: 7 days
- Justification for the choice of the species: standard experimental animal
- Animal identification: marked by numbered ear tags and individual cage cards (project number, test group, animal number, ear tag number, source, stain, sex, date of receipt)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 °C ± 1.5 °C
- Humidity (%): 65 % ± 10 %
- Recording: by thermohygrograph
- Air changes (per hr): 16 times
- Photoperiod (hrs dark / hrs light): 12/24 from 7.00 a.m to 7.00 p.m.
- Intensity of light: 120 lux

Route of administration:

oral: feed

Vehicle:

other: basal diet ( incorporation in pellet)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS DIET PREPARATION
- Rate of preparation of diet: the mixtures were prepared for the first 6 study weeks and again for the 6-13 weeks study phase.
- Mixing: test compound was weighted out for each concentration level and mixed with a small amount of basal diet (300 g), in a pulverized form. Mixing was continued in three steps to the final quantity. Each preparation was pelleted and identified.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Randomized collected samples from each batch and dose level were analysed for N-Oleyl Palmitamide concentrations (Identity, concentration, homogeneity and stability) by Dr. J.G.A. Kooyman, Clo AKZO Chemicals, Netherland BV, Research Centre Deventer, Analytical Department, Deventer.
- Results: the N-Oleyl Palmitamide concentrations were within a range of 10% of the target, homogeneity was within 10% of the average of Samples and stability was not deviating more than 7% of the originally determined average content.
- Basal diet (control) samples were analyzed to confirm the absence of N-Oleyl Palmitamide.
- Stability of the high concentration was tested after storage of the diet for 6 weeks and 4 months.

Duration of treatment / exposure:

13 weeks

Remarks:

Doses / Concentrations:
1200
Basis:
other: dietary concentration of N-Oleyl Palmitamide (ppm)

Remarks:

Doses / Concentrations:
6000
Basis:
other: dietary concentration of N-Oleyl Palmitamide (ppm)

Remarks:

Doses / Concentrations:
12000
Basis:
other: dietary concentration of N-Oleyl Palmitamide (ppm)

No. of animals per sex per dose:

40 male/40 female
4 test groups of 10 male and 10 female animals

Control animals:

yes, concurrent no treatment

Details on study design:

- Rationale for animal assignment: random, by a computerized randomization table (from both sexes)

Observations and examinations performed and frequency:

CLINICAL OBSERVATION
All animals were observed daily with regard to their Sensory and motor behaviour, hair coat, body orifices, urine and faecal excretion, for their general health status and dose responses. The observations were recorded daily and dose responses were summarized in weekly reports. Viability or mortality checks, resp., were performed twice daily.
SPECIAL CLINICAL EXAMINATION (by Dr. Trinks)
Prior to initiation, after 6 weeks and at termination:
- Ophthalmologic examinations: (cornea, episceral vessels, anterior chamber, pupil, lens, retina) using an ophthalmoscope
- The hearing, tested by simple noise production
- The reflex (awareness, emotion, coordination, autonomic functions)
In weekly intervals:
- Bodyweights, food consumption, water consumption
At the end of the test:
- Moribund animals/mortalities
- Complete macroscopic autopsy
- Organs observations
LABORATORY EXAMINATION (IBR laboratory)
After 6 weeks and at termination
- Hematologiacal and clinical chemistry investigations (samples from retrobulbar venous plexus)
- Urine collection (collected in 18 hours after 20 ml/Kg intragastric administration of water)

Sacrifice and pathology:

NECROPSY
All surviving animals were sacrificed at the end of the experiment by C02 asphyxiation.
A complete autopsy was performed for each animal, with the order of necropsy performed in a random manner (macropathological observations, registration of any abnormal findings)
DETERMINATION OF ORGAN WEIGHTS

Other examinations:

HISTOPATHOLOGICAL EXAMINATIONS (after organ fixation and tissue preparation)

Statistics:

Scheffè method for weight changes, food consumption and water consumption
Co-variance analysis and Scheffè method for organ weights
Variance analysis for dose-effect curves and Scheffè method for clinical chemistry and hematology
Results are expressed with the mean values per group and the standard deviation.
For bodyweights the percentage is calculated.
All control mean values are equalized with 100 %.

Clinical signs:

no effects observed

Description (incidence and severity):

Special reflex examinations after 6 weeks and at termination did not reveal any differences between control- and dose group animals

Mortality:

no mortality observed

Description (incidence):

Special reflex examinations after 6 weeks and at termination did not reveal any differences between control- and dose group animals

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Slight variations among groups were within a range of 10 % to the controls and, since there was no evidence of dose-relation

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

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Description (incidence and severity):

Some sporadic differences were not dose-related and thus considered to be coincidental.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Occasionally occurring significant differences to the concurrent control group were not specifically dose-related

Urinalysis findings:

no effects observed

Description (incidence and severity):

The significant decrease of specific gravity in dose group III (males) after 6 weeks was not dose-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Description (incidence and severity):

Some incidental spontaneous changes were nearly equally distributed among control and dose group animals

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Some spontaneous incidental lesions or lesions due to sacrifice were found

Histopathological findings: neoplastic:

not examined

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

other: dietary concentration

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOEL

Effect level:

12 000 ppm

Based on:

other: dietary concentration

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

The test material was incorporated into pelleted rat standard laboratory diet at concentrations of 1200 ppm (dose group I), 6000 ppm (dose group II) and 12000 ppm (dose group III), to perform a test according to OECD 408. 

These dietary concentrations were designed to provide daily dose levels of 100, 500, and 1000 mg/kg/day.

A concurrent control group received the basal diet only. Eachgroup consisted of 10 Wistar-rats per sex. The rats were exposed to the testcompound over an entire test period of 13 weeks. Analytical chemistry results indicated that the mixing procedure resulted in homogeneous mixtures of the test material in the diet. Periodic analyses during the study found the concentrations of test material in the diet to be within acceptable limits. A stability study conducted at the high concentration after storage for up to 4 months indicated that the test material was stabile in the diet. Under the experimental conditions of the study the test material had no adverseeffects on clinical signs, bodyweights, food consumption, water consumption,hematology, clinical chemistry, organs weights, and histopathology.

The "no-effect" - level of the test material was at a dietary concentrationof 12000 ppm, when fed to rats of the Wistar-strain over an entire test period of 13 weeks.

This no-adverse effect level correlates with a mean test compound intake of approximately 1000 mg/Kg/day.

 

Samples from all tissues listed below were removed from all animals; blocks and slides were prepared and examined for the control and high dose groups: skin, mammary gland, salivary gland, trachea, esophagus, thyroid (2x), parathyroid (2x), thymus, heart, lung, aorta, pituitary, tongue, liver, spleen, pancreas, kidney (2x), adrenal (2x), stomach, duodenum, jejunum, ileum, cecum, colon, seminal vesicle, lymph node (mesenteric+ cervical), ovary (2x)/ testis + epididymis (2x), prostate/uterus + vagina, urinary bladder, sciatic nerve, skeletal muscle, bone with marrow (sternum + femur), eye with N. opticus (2x), cerebrum with brain stem, cerebellum, spinal cord (2x), lacrimal gland (2x), macroscopic changes.

Microscopic evaluation of representative organ sections from all control and high dose animals did not reveal any test item related changes. Some spontaneous incidental lesions or lesions due to sacrifice were found evenly distributed among control and high dose animals of both sexes.

Conclusions:

The results of this study indicate, that the test material had no adverse effect on any of the tested parameters in rats of the Wistar-strain over the entire test period of 13 weeks. Thus a dietary concentration of 12000 ppm (high-dose group) revealed a clear "no-effect" level.
Significant intergroup differences in individual parameters were generally within normal limits and without any dose-relationship. These differences are therefore considered to be without biological importance and not attributable to the test material exposure.

Executive summary:

In an OECD 408 study, conducted according to GLP, the sub-chronic toxicity of the structurally similar read across substance in male and female Wistar rats a NOAEL of greater than or equal to 1,000 mg/kg/d was determined. The lack of test item related changes in the reproductive organs, accessory sexual organs, pituitary, adrenal gland, and thyroid provides evidence that the substance lacks the potential to cause reproductive toxicity and no treatment-related histopathological, haematological or clinical effects were observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

1

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

14-day repeated-dose toxicity study: oral (registered substance)

The test material was well tolerated in Han Wistar rats at oral doses up to 1000 mg/kg/day. All animals survived to scheduled sacrifice. There were no treatment-related effects in clinical observations and no macroscopic changes at necropsy.

The decrease in overall body weight gain and food consumption in males at 1000 mg/kg/day and females at 500 or 1000 mg/kg/day was minimal. It was concluded that oral doses up to 1000 mg/kg/day would be a suitable high dose level for the subsequent prenatal developmental toxicity study, and/or general toxicity studies of longer duration.

 

90-day repeated-dose toxicity study: oral (analogue)

The sub-chronic toxicity of the structurally similar read across substance in male and female Wistar rats a NOAEL of greater than or equal to 1,000 mg/kg/d was determined. The lack of test item related changes in the reproductive organs, accessory sexual organs, pituitary, adrenal gland, and thyroid provides evidence that the substance lacks the potential to cause reproductive toxicity and no treatment-related histopathological, haematological or clinical effects were observed.

Justification for classification or non-classification

In an OECD 408 study, conducted according to GLP with the read-across substance the NOAEL was 1,000 mg/kg bw/d.

According to Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP), the registered substance does not meet the criteria for classification.