Registration Dossier

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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
This 14 d study, intended to be a dose-ranging study to identify doses to be used in a subsequent 90 d study.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Principles of method if other than guideline:
duration: 14 d
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Sprague-Dawley rats (Vivo Bio Tech Ltd), age: 6–7 weeks
Route of administration:
oral: gavage
Vehicle:
other: water with Tween 80 (0.5 % w/v) and carboxymethyl cellulose (1 % w/v)
Details on oral exposure:
Preliminary tests found that the test substance was suitable for oral gavage by suspension in water with Tween 80 (0.5 % w/v) as a surfactant and carboxymethyl cellulose (1 % w/v) as a suspending agent.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses performed to verify the concentrations of the test substance in dosing formulations in the 90-day study showed that they were within an acceptable range compared to their respective nominal concentrations.
Duration of treatment / exposure:
14 d
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
five of each sex
Control animals:
yes
Details on study design:
The following observations and examinations were performed: mortality and clinical signs – daily, body weight and food consumption – weekly. Additionally samples for hematology and clinical chemistry analysis were taken just prior to sacrifice, and gross necropsy was performed, recording any gross pathological observations and organ weights.
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:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
Key result
Critical effects observed:
no
Conclusions:
Under the study conditions, the NOEL from this study was >1000 mg/kg bw/day.
Executive summary:

A study was conducted to determine repeated dose toxicity of the test substance according to a design based on OECD Guideline 407. This 14 d study intended to identify the dose-range to be used in a subsequent 90 d study. Preliminary tests found that the test substance was suitable for oral gavage by suspension in water with Tween 80 (0.5% w/v) as a surfactant and carboxymethyl cellulose (1% w/v) as a suspending agent. Ten Sprague-Dawley rats, five of each sex, were dosed with a vehicle control and with the test substance at 100, 300, and 1000 mg/kg bw/day daily through duration of the study. Observations for mortality and clinical signs were made daily and of body weight and food consumption weekly. Additionally samples for hematology and clinical chemistry analysis were taken just prior to sacrifice, and gross pathology was performed. Analyses performed to verify the concentrations of the test substance in dosing formulations in the 90-day study showed that they were within an acceptable range compared to their respective nominal concentrations. No incidence of clinical signs or death was found following 14 days of treatment with the test substance at 0, 100, 300, or 1000 mg/kg bw/day. Furthermore, no adverse effects were observed on body weight gain, food consumption, hematological parameters, clinical chemistry, gross pathology, or on absolute or relative organ weights. Under the study conditions, the NOEL from this study was >1000 mg/kg bw/day (Nestmann, 2017).

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Sprague-Dawley rats (Vivo Bio Tech Ltd), age: 6–7 weeks
Route of administration:
oral: gavage
Vehicle:
other: water with Tween 80 (0.5 % w/v) and carboxymethyl cellulose (1 % w/v)
Details on oral exposure:
Preliminary tests found that the test substance was suitable for oral gavage by suspension in water with Tween 80 (0.5 % w/v) as a surfactant and carboxymethyl cellulose (1 % w/v) as a suspending agent.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses performed to verify the concentrations of the test substance in dosing formulations showed that they were within an acceptable range compared to their respective nominal concentrations.
Duration of treatment / exposure:
90 d
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20 (10 males and 10 females)
Control animals:
yes
Details on study design:
Rats were divided into six groups. Four groups of 20 (10 males and 10 females) were treated for 90 d by oral gavage with the vehicle control, the low dose of 250 mg/kg bw/day, the mid dose of 500 mg/kg bw/day, or the high dose of 1000 mg/kg bw/day. An additional 10 animals (five males and five females) in the control and in the high-dose groups were allowed to recover for an additional 28 days.
Observations and examinations performed and frequency:
Observations:

Mortality (daily), clinical signs (weekly),
Ophthalmological examinations: before study initiation and at study termination,
Neurological parameters: qualitative and quantitative assessment of sensory reactivity, grip strength, motor activity, frequency of urination, defecation, rearing, and landing foot splay,
Body weight and food consumption: weekly,
Samples for hematology and clinical chemistry analysis: taken just prior to sacrifice.


Hematological parameters include hematocrit, hemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, and blood clotting time.

Clinical chemistry determinations include sodium, potassium, glucose, total cholesterol, urea, blood urea nitrogen, creatinine, total protein and albumin, and two or more enzymes that indicate hepatocellular effects.

Urine samples taken during the last week before sacrifice are examined for appearance, volume, osmolality or specific gravity, pH, protein, glucose, and presence of blood or blood cells.

Sacrifice and pathology:
At study termination, gross necropsy is performed including complete external body examination and organ weights recorded for liver, kidneys, adrenals, testes, epididymides, uterus, ovaries thymus, spleen, brain, and heart.
Histopathological examination is performed on tissue samples from: all gross lesions, representative brain regions, spinal cord at three levels, pituitary, thyroid, parathyroid, thymus, esophagus, salivary glands, stomach, small and large intestines (including Peyer’s patches), liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, gonads, uterus, accessory sex organs, female mammary gland, prostate, urinary bladder, lymph nodes, peripheral nerve, bone marrow section, skin, and eyes if changes were observed upon examination. Tissue samples are fixed in 10 % neutral buffered formalin before embedding in paraffin wax. Sections of 5 μm thickness are stained with hematoxylin and eosin for microscopic examination.
Statistics:
The results were analyzed statistically with IBM SPSS Statistical Software (version 23). Following assessment of homogeneity, using Levene’s test, of body weight, food consumption, hematology, clinical chemistry, organ weight, and neurological examination data, different groups were subjected to one-way analysis of variance (ANOVA). Comparisons between treated and control groups were analyzed by t tests with variance evaluated at the 5 % level of significance.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No clinical signs were found in any group other than respiratory rales in one control male (day 84 until termination at day 91) and one treated, mid-dose (500 mg/kg bw/d) male from day 80 until day 91; these observations were incidental, not dose-related, and of no toxicological significance.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The average weight of male animals in the high treatment recovery group, was less than the average of males in the control recovery group, a difference that was statistically significant (P < 0.05). Based on the combined data from all dose groups and food consumption data, it is concluded that consumption of the test substance did not have an adverse effect on body weight or body weight gain.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
The results are normal with no differences between control and treated groups except for elevated total WBC counts for the high-dose group at the end of the recovery period. Although statistically higher than concurrent controls, the value 10.08+E3/cm2 is well within the historical range for control rats in 90-day studies at the test facility.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
A few isolated measurements were statistically different from controls, but are considered to be incidental and without biological significance due to lack of any dose dependency as well as their values falling within ranges of the laboratory’s historical controls.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
The only statistically significant difference in mean organ weights noted at end of the 90 d treatment was that of the relative, but not absolute, heart weight in females being lesser than the control, which in absence of dose dependence, was considered to be incidental. At the end of the 28 d recovery period, absolute and relative adrenal weights only in male rats were statistically higher in the high dose group as compared to controls, and absolute liver weights were significantly lower in the highest dose group females only than in control rats. These results appear to be incidental due to the lack of any changes in other correlated parameters, such as necropsy findings, histopathology findings, clinical hematology, and clinical chemistry.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Gross necropsy revealed an absence of any remarkable gross abnormalities in all but two male animals at the end of the 90 d treatment period and two males at the end of the 28 d recovery phase. One mid-dose rat had multiple abscesses in the lungs and another mid dose rat animal had underweight testes and epididymides. These incidental findings were found only in this group and are concluded to be unrelated to dosing with the test substance. Moderate splenic enlargement was found in two high dose males at the end of the recovery period, but subsequent histopathologic examination showed this to be due to splenic congestion, a common condition considered to be incidental in this case.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
The evaluation of tissues and organs from control and high-dose groups showed no incidence of any remarkable findings that could be related to treatment due to lack of any dose dependency as well as their values falling within ranges of the laboratory’s historical controls. Single animals in different groups showed isolated (1 in 20 animals) findings.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
Key result
Critical effects observed:
no
Conclusions:
Under the study conditions, no treatment-related adverse effects were found and the NOEL was considered to be the highest dose level of 1000 mg/kg bw/day.
Executive summary:

A study was conducted to determine repeated dose toxicity of the test substance according to design based on OECD Guideline 408, in compliance with GLP. Preliminary tests found that the test substance was suitable for oral gavage by suspension in water with Tween 80 (0.5% w/v) as a surfactant and carboxymethyl cellulose (1% w/v) as a suspending agent. Sprague-Dawley rats were divided into six groups. Four groups of 20 (10 males and 10 females) were treated for 90 d by oral gavage with the vehicle control, the low dose of 250 mg/kg bw/day, the mid dose of 500 mg/kg bw/day, or the high dose of 1000 mg/kg bw/day. An additional 10 animals (five males and five females) in the control and in the high-dose groups were allowed to recover for an additional 28 d. The following observations and examinations were performed: mortality (daily), clinical signs (weekly), functional observations and locomotor activity (end of treatment), body weight and food consumption (weekly), clinical pathology (end of treatment), ophthalmological examinations (before study initiation and at study termination), macroscopy at termination, organ weights and histopathology on a selection of tissues. There were some incidental findings that are concluded to be unrelated to treatment and of no toxicological significance. Under the study conditions, no treatment-related adverse effects were found and the NOEL was considered to be the highest dose level of 1000 mg/kg bw/day (Nestmann, 2017).

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read across study
Remarks:
Not GLP
Justification for type of information:
Refer to Section 13 for details on the read across justification.
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
not specified
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Mus-Rattus, Brunntal, Germany
- Age at study initiation: between 6-7 wk
- Weight at study initiation: 111 (f) - 125 (m) g
- Housing: plastic cages, 3 males and 5 females/cage
- Diet (e.g. ad libitum): ad libitum (Altromin Ratdiet No. 1424 DK, Altromin GmbH, Lage, Germany)
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: 6 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-20
- Humidity (%): 60-75
- Air changes (per hr): 11
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
doses were adpated weekly to the body weight
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 d
Frequency of treatment:
daily once, 5 times/wk
Remarks:
Doses / Concentrations:
70 mg/kg bw/d (Days 1-28)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
250 mg/kg bw/d (Days 1-28)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
750 mg/kg bw/d (Days 1-14)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1500 mg/kg bw/d (Days 15-28)
Basis:
actual ingested
No. of animals per sex per dose:
10/sex/dose for main study; 5/sex/dose for 4 month recovery period
Control animals:
yes, concurrent no treatment
Details on study design:
according to standard procedure
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: end of study


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of study
- Anaesthetic used for blood collection: Yes (ether)
- How many animals: 10 per dose and sex
- Parameters checked: Hematocrit, erythrocytes, leukocytes, hemoglobin, thrombocytes, mean corpuscular volume, white blood cell differntial


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of study
- How many animals: 10 per sex and dose
- Parameters checked: GPT, GOT, AP, glucose, urea, total protein, calcium, phosphate, cholestrol


URINALYSIS: Yes
- Time schedule for collection of urine: end of study
- Metabolism cages used for collection of urine: No
- Parameters checked: urea, creatinin, sodium, potassium, glucose, calcium, ap


NEUROBEHAVIOURAL EXAMINATION: No


Other: Groups of 5 male and 5 female rats kept for an additional 4 month recovery period.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
the following tissues/organs were examined:
adrenal gland (2)
aorta thoracica
brain (cornu ammonis)
coagulating gland with seminal vesicle
epididymis (2)
eye with optic nerve (2)
heart
intestine, large
intestine, small
kidney (2)
liver
lungs
lymph node (cervical) (1)
lymph node (mesenteric) (1)
mucles
oesophagus
ovary (2)
pancreas
prostate
salivary glands (mandibular,
parotid and sublingual gland)
skin
spleen
stomach
testicle (2)
thymus
thyroid (2) (incl. parathyroids)
tongue
trachea (incl. larynx)
urinary bladder
uterus (incl. cervix and oviducts)



HISTOPATHOLOGY: Yes
see gross pathology
Statistics:
't' test used for statistical analysis of all parameters except organ weight (U-test)
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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
The doses up to 1500 mg/kg bw/d were tolerated by all animals without lethality. The body weight gain and total increase of body weights did not differ from the control group. Absolute and relative organ weights showed no significant changes in the substance groups compared to the control group, accept the organ weight of the adrenal gland which is increased for the females of group 3 (250 mg/kg) and 4 (750/1500 mg/kg bw). This result is considered of no relevance. The pathological, histological evaluation did not show significant compound related gross or microscocopic organ injury of liver, kidneys, adrenals, heart, lung, spleen and gonads; dose independent reversible local findings were restricted to the fore stomach mucose of the highest group (hyperplastic and cellular changes in the forestomach but not dose-related and also found in controls. Attributed to the use of olive oil as carrier. Effects disappeared during 4 month recovery period). The biochemical parameters calcium, blood sugar, urea, creatinine, cholesterine, GGT, GOT, GPT and LDH did not show any irregular signs. Slight alterations of phosphate in the highest group were noted and regarded as dose/compound related but not critical effect.
Key result
Dose descriptor:
NOAEL
Effect level:
> 750 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No biologically relevant effects observed on any of the parameters recorded at any dose. Also, test animals treated with 1500 mg/kg bw /d (Day 15-28) showed no adverse effect
Key result
Critical effects observed:
no
Conclusions:
Under the study conditions, the systemic NOAEL was considered to be >750 mg/kg bw.
Executive summary:

A study was conducted to determine the repeated dose oral toxicity of the read across substance, amides, C12-18 (even-numbered) and C18-unsatd., N-(hydroxyethyl), to rats according to a method similar or equivalent to OECD Guideline 407. Groups of 10 male and 10 female rats were orally gavaged with the test substance diluted in olive oil 5 d/wk at 0, 70, 250, 750 (Days 1-14) or 1500 (Days 15-28) for 28 d. Clinical signs, bodyweight, hematology, clinical chemistry, urinalysis, gross and microscopic pathology were recorded. Additional groups of 5 male and 5 female rats were kept for a 4 month recovery period. No treatment-related adverse effects were observed at any of the doses. Changes in the forestomach at some doses including controls were attributed to the use of olive oil and found to be reversible after end of exposure. The doses up to 1500 mg/kg bw/d were tolerated by all animals without lethality. The body weight gain and total increase of body weights did not differ from the control group. The pathological, histological evaluation did not show significant compound related gross or microscopic organ injury of liver, kidneys, adrenals, heart, lung, spleen and gonads. Dose-independent reversible local findings were restricted to the fore stomach mucosa of the highest group. The biochemical parameters calcium, blood sugar, urea, creatinine, cholesterol, GGT, GOT, GPT and LDH did not show any irregular signs. Slight alterations of phosphate in the highest group were noted and regarded as dose/compound related but not critical effect. Hence, under the study conditions, the systemic NOAEL was considered to be >750 mg/kg bw (Gloxhuber, 1983).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
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 d study

A study was conducted to determine repeated dose toxicity of the test substance according to a design based on OECD Guideline 407. This 14 d study intended to identify the dose-range to be used in a subsequent 90 d study. Preliminary tests found that the test substance was suitable for oral gavage by suspension in water with Tween 80 (0.5% w/v) as a surfactant and carboxymethyl cellulose (1% w/v) as a suspending agent. Ten Sprague-Dawley rats, five of each sex, were dosed with a vehicle control and with the test substance at 100, 300, and 1000 mg/kg bw/day daily through duration of the study. Observations for mortality and clinical signs were made daily and of body weight and food consumption weekly. Additionally samples for hematology and clinical chemistry analysis were taken just prior to sacrifice, and gross pathology was performed. Analyses performed to verify the concentrations of the test substance in dosing formulations in the 90-day study showed that they were within an acceptable range compared to their respective nominal concentrations. No incidence of clinical signs or death was found following 14 days of treatment with the test substance at 0, 100, 300, or 1000 mg/kg bw/day. Furthermore, no adverse effects were observed on body weight gain, food consumption, hematological parameters, clinical chemistry, gross pathology, or on absolute or relative organ weights. Under the study conditions, the NOEL from this study was >1000 mg/kg bw/day (Nestmann, 2017).

 

90 d study

A study was conducted to determine repeated dose toxicity of the test substance according to design based on OECD Guideline 408, in compliance with GLP. Preliminary tests found that the test substance was suitable for oral gavage by suspension in water with Tween 80 (0.5% w/v) as a surfactant and carboxymethyl cellulose (1% w/v) as a suspending agent. Sprague-Dawley rats were divided into six groups. Four groups of 20 (10 males and 10 females) were treated for 90 d by oral gavage with the vehicle control, the low dose of 250 mg/kg bw/day, the mid dose of 500 mg/kg bw/day, or the high dose of 1000 mg/kg bw/day. An additional 10 animals (five males and five females) in the control and in the high-dose groups were allowed to recover for an additional 28 d. The following observations and examinations were performed: mortality (daily), clinical signs (weekly), functional observations and locomotor activity (end of treatment), body weight and food consumption (weekly), clinical pathology (end of treatment), ophthalmological examinations (before study initiation and at study termination), macroscopy at termination, organ weights and histopathology on a selection of tissues. There were some incidental findings that are concluded to be unrelated to treatment and of no toxicological significance. Under the study conditions, no treatment-related adverse effects were found and the NOEL was considered to be the highest dose level of 1000 mg/kg bw/day (Nestmann, 2017).

 

Read across 28 d study

A study was conducted to determine the repeated dose oral toxicity of the read across substance, amides, C12-18 (even-numbered) and C18-unsatd., N-(hydroxyethyl), to rats according to a method similar or equivalent to OECD Guideline 407. Groups of 10 male and 10 female rats were orally gavaged with the test substance diluted in olive oil 5 d/wk at 0, 70, 250, 750 (Days 1-14) or 1500 (Days 15-28) for 28 d. Clinical signs, bodyweight, hematology, clinical chemistry, urinalysis, gross and microscopic pathology were recorded. Additional groups of 5 male and 5 female rats were kept for a 4 month recovery period. No treatment-related adverse effects were observed at any of the doses. Changes in the forestomach at some doses including controls were attributed to the use of olive oil and found to be reversible after end of exposure. The doses up to 1500 mg/kg bw/d were tolerated by all animals without lethality. The body weight gain and total increase of body weights did not differ from the control group. The pathological, histological evaluation did not show significant compound related gross or microscopic organ injury of liver, kidneys, adrenals, heart, lung, spleen and gonads. Dose-independent reversible local findings were restricted to the fore stomach mucosa of the highest group. The biochemical parameters calcium, blood sugar, urea, creatinine, cholesterol, GGT, GOT, GPT and LDH did not show any irregular signs. Slight alterations of phosphate in the highest group were noted and regarded as dose/compound related but not critical effect. Hence, under the study conditions, the systemic NOAEL was considered to be >750 mg/kg bw (Gloxhuber, 1983).

Justification for classification or non-classification

Based on the results of repeated dose oral toxicity studies with the substance itself and with the read across substance amides, C12-18 (even-numbered) and C18-unsatd., N-(hydroxyethyl), no classification for this endpoint is required according to CLP (EC 1272/2008) criteria.