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EC number: 292-960-4 | CAS number: 91031-57-1
- 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
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- Endpoint summary
- Stability
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- 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
Endpoint summary
Administrative data
Description of key information
Oral (OECD 422, read across): NOAEL female rat = 300 mg/kg bw/day
Oral (OECD 422, read across): NOAEL male rat = 1000 mg/kg bw/day
Oral (OECD 407, read across): NOAEL, male and female rat >1000 mg/kg bw/day
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- Refer to analogue justification provided in IUCLID section 13.
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across source
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other:
- Remarks:
- Source: CAS 59231-34-4
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- Source: CAS 59231-34-4
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- Source: CAS 91031-48-0
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- Source: CAS 3687-46-5
- Key result
- Critical effects observed:
- no
- Conclusions:
- CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 01 Nov - 13 Dec 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 22 Mar 1996
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Behoerde fuer Soziales, Familie, Gesundheit und Verbraucherschutz; Hamburg, Germany
- Limit test:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Research Models and Services Germany GmbH, Sulzfeld, Germany
- Age at study initiation: males: 50 days; females: 60 days
- Mean weight at study initiation: males: 248.8 to 298.7 g; females: 195.2 to 228.1 g
- Fasting period before study: no
- Housing: single housing in MAKROLON cages (type III plus)
- Diet: commercial ssniff R-Z V1324 (ssniff Spezialdiäten GmbH, Soest, Germany); ad libitum
- Water: tap water; ad libitum
(Analyses of diet and water was performed.)
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 15
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- VEHICLE
- Concentration in vehicle: 50, 150 and 500 mg/mL
- Amount of vehicle (if gavage): 2 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- For the analysis of the test item-vehicle mixtures samples were taken at the following time points and stored at ≤ -20°C until analysis:
Start of treatment period; immediately after preparation of the test item-vehicle mixtures; 8 and 24 hours after storage of the test item preparations at room temperature; end of treatment period; during treatment with the test item always before administration to the last animal of the dose level group
The following parameters were determined: linearity, accuracy, precision, sensitivity, specificity, stability at +2°C to +8°C or -20°C (0, 24, 72 and 168 hours) - Duration of treatment / exposure:
- Males: The daily administration of the test item was started two weeks before mating and lasted until test day 35, which was one day before sacrifice.
Females: The daily administration of the test item was started two weeks before mating and continued to at least day 3 of lactation.
Maximum: 56 days of treatment - Frequency of treatment:
- once daily; 7 days/week
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on a 14-day range-finding study (Leuschner, 2012)
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: before and after dosing
- Cage side observations checked: skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns
MORTALITY AND CLINICAL SIGNS
- Time schedule: at least once daily (the frequency was increased when signs of toxicity were observed); deaths were recorded twice daily (animals which died or were sacrificed during the study were necropsied as soon as possible after exitus)
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before the first exposure (to allow within-subject comparisons) and once a week thereafter
- Paramters: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lacrimation, pilo-erection, pupil size, and unusual respiratory pattern); changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. self-mutilation, walking backwards)
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily by visual appraisal
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations:
- Dose groups that were examined: all dose groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the pre-mating period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes, overnight
- How many animals: 5/sex/dose
- Parameters: haemoglobin, erythrocytes, leucocytes, differential blood count (absolute/relative), reticulocytes, platelets, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, thromboplastin time, activated partial thromboplastin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the pre-mating period
- Animals fasted: Yes, overnight
- How many animals: 5/sex/dose
- Parameters examined: albumin, globulin, albumin/globulin ratio, bile acids, bilirubin, cholesterol (total), creatinine, glucose, urea, total protein, calcium, chlorid, potassium, sodium, alanine aminotransferase (ALAT), alkaline phosphatase (AP), aspartate aminotransferase (ASAT)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: two hours after dosing shortly before scheduled sacrifice in 5 males per group (day 35); two hours after dosing during lactation, shortly before scheduled sacrifice in 5 females per group (day 39-56)
Screening of assessment were conducted as described on the following pages in five males and five females randomly selected from each group.
- Dose groups that were examined: all dose groups
- Battery of functions tested: sensory reactivity to stimuli of different types (e.g. auditory, visual and proprioceptive stimuli) (based on Gad), as well as the assessment of grip strength (Meyer) and motor activity
OTHER: Qualitative sperm analysis was performed.
(for further reproduction parameters see respective study entry (chapter 7.8.1))
Males were sacrificed on day 36, females were sacrifices on day 4 post-partum or shorty thereafter. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- Organ weights: epididymes and testicles (all males); adrenal gland, brain, heart, kidney, liver, spleen, thymus (5/sex/dose)
- Fixation: epididymis, gross lesions, mammary gland, ovary, prostate, seminal vesicle, testicle, uterus (incl. cervix and oviducts), vagina (all animals); adrenal gland, bone marrow (os femoris), brain (cerebrum, cerebellum, brain stem), heart (left and right ventricle, septum), intestine, small (duodenum, jejunum, ileum, incl. Peyer's patches, Swiss roll method), intestine, large (colon, rectum), kidney and ureter, liver, lungs (with mainstem bronchi and bronchioles), preserved by inflation with fixative and then immersion, lymph node (1 cervical, 1 mesenteric), nerve (sciatic), oesophagus, spinal cord (3 sections), spleen, stomach, thyroid (incl. parathyroids), thymus, tissue masses or tumours (incl. regional lymph nodes), tongue (incl. base), trachea (incl. larynx), urinary bladder (5/sex/dose)
HISTOPATHOLOGY: Yes, all organs that were included for fixation (5/sex of control and high dose group) - Statistics:
- STUDENT's t-test (p ≤ 0.01): all numerical functional tests
Multiple t-test based on DUNNETT (p≤0.05 and p ≤ 0.01): body weight, food consumption, haematology, clinical chemistry, absolute and relative organ weights
For all numerical values homogeneity of variances was tested by using the BARTLETT chi-square test. If the variances were homogeneous, the DUNNETT test (p ≤ 0.01) was used to compare the experimental groups with the control group. In case of heterogeneity of variances, the STUDENT's t-test was carried out; limit of significance was p ≤ 0.01. - Clinical signs:
- no effects observed
- Description (incidence and severity):
- Piloerection was seen in 1 female of the high dose group on day 2-4 of lactation.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- statistically significant decrease (-9.4%) in body weight in females during lactation at 1000 mg/kg bw/day
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- In the high dose group (females: gestation/lactation period) a statistically significant reduction in food consumption by 21.7% was noted.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- An decrease of ASAT activity was seen in high dose females on day 15. This effects was considered to be due to the relative low or high value observed for the control group and not to be test item related.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- All effects observed (slight increase in absolute and relative liver weight in males) were still within the historical control data of the laboratory and thus not of toxicological relevance.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- The qualitative sperm staging revealed no test item-related specific spermatogenic changes in the male animals from the high dose group (1000 mg/kg b.w./day).
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 16 Nov 1982 - 19 Jan 1983
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- No monitoring of clinical signs outside the home cage, no neurobehavioural examinations.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- no monitoring of clinical signs outside the home cage, no neurobehavioural examinations
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Wistar Han.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Züchter Zentralinstitut für Versuchstiere, Hannover, Germany
- Age at study initiation: approximately 4 weeks
- Weight at study initiation: 50-78 g (males); 50-82 g (females)
- Housing: 2-3 animals/sex/cage in Macrolon cages (type III) with wood shavings (Arwi-Center, Essen, Germany)
- Diet: Altromin 1324 DK pelleted, nitrosamine-poor diet (Fa. Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (ºC): 21-22
- Humidity (%): 49-65
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The dosing solutions were prepared daily prior to administration. The application volumes were adapted weekly to the current body weights.
VEHICLE
- Concentration in vehicle: 2, 10 and 20% in olive oil for the 100, 500 and 1000 mg/kg bw/day groups, respectively
- Amount of vehicle (if gavage): 5 mL/kg bw - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 28 days (21 doses) and 28 days post-exposure observation period (satellite control and treated groups)
- Frequency of treatment:
- Daily, 5 days/week
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10 (main groups, control and all dose levels)
5 (satellite groups, control and all dose levels) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Post-exposure recovery period in satellite groups: 28 days. A satellite groups was included in the control group and each dose group.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations examined: mortality, clinical signs
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION : Yes. Determined per cage per week.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: Yes. Determined per cage per week.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to necropsy
- Dose groups that were examined: all dose groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to necropsy
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: No data
- How many animals: all dose groups
- Parameters examined: haematocrit, haemoglobin content, red blood cell count, white blood cell count, mean cell volume, thrombocyte cell count, differential blood count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to necropsy
- Animals fasted: No data
- How many animals: all dose groups
- Parameters examined: urea, creatinine, glucose, sodium, potassium, calcium, inorganic phosphorus, alkaline phosphatase, serum alanine aminotransferase, serum aspartate aminotransferase, gamma glutamyl transpeptidase, chloride, albumin, total protein, cholesterol
URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the study period
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: pH, proteins, glucose, blood cells, bacteria, leucocytes, erythrocytes, urea, sodium oxide, urobilin, ket., specific gravity, epi., trip.
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: faeces were collected at the end of the study and examined for parasites, appearance and amount. - Sacrifice and pathology:
- GROSS PATHOLOGY:
Yes. Gross pathology was performed in all animals, including the satellite group animals. The absolute and relative weight of the following organs was determined: thyroid, adrenals, thymus, spleen, heart, kidneys, brain, testes, ovaries and liver.
HISTOPATHOLOGY:
Yes, in all animals in the control and 1000 mg/kg bw/day groups the following organs were examined: brain (cerebrum, cerebellum), eye, tongue, salivary glands, auxillary lymph nodes, oesophagus, trachea, heart, aorta, lungs, bronchial lymph nodes, liver, spleen, kidneys,
urethra, pancreas, thymus, thyroid, parathyroid, adrenals, peripheral nerve, forestomach, stomach, duodenum, jejunum, ileum, colon, caecum, rectum, anal mucosa, Peyer's patches, mesenterial lymph node, gall bladder, urinary bladder, vagina, uterus, ovary, prostate, testes, epididymes, prostate + seminal vesicles with coagulating glands, skin, muscle, skin lymph nodes, mammary gland.
The target organ of the main groups was the liver, which was examined in greater detail in 3 male and 3 female animals in the control and 1000 mg/kg bw/day groups. In the satellite groups, the target organs (lungs, pancreas, maxillary lymph node, salivary gland and forestomach) were examined in 3 females and males from the control and 1000 mg/kg bw/day satelllite groups. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The body weight was statistically significantly lower in the male 100 mg/kg bw/day group in week 0 and 1. As the rats weighed, on average, less from the start of the study, this reflects a mistake in standardising the group and is not related to the treatment (see Table 1).
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- The food consumption in females and males administered 1000 mg/kg bw/day was statistically significantly increased in week 2, while in the males in this dose group the intake was reduced in week 3. Both males and females in the 500 mg/kg bw/day group had a statistically significant increase in food consumption in week 2. These effect were transient and were considered not to be treatment-related (see Table 1).
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- The water intake was statistically significantly increased in males in the highest dose group in week 2. For males administered 100 mg/kg bw/day the intake was decreased in week 1 and 2. In the female groups, the water consumption was reduced with statistical significance in females administered 100, 500 and 1000 mg/kg bw/day in week 2, week 3 and 4, and week 3, respectively. These effect were transient and were considered not to be substance-related (see Table 1).
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significant decreases in haemoglobin levels were observed in all dose groups. As the changes were not dose-related and no other relevant effects were seen in histopathological parameters, this is not considered to be a toxicologically relevant effect. A reduction in the haematocrit level and red blood cell count in the 500 mg/kg bw/day females was considered to be incidental as the effect was only observed at one dose level and in one sex.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The inorganic phosphorus level was increased with statistical significance in all male dose groups and in the 100 and 500 mg/kg bw/day female group. The effect was not dose-related in the males and not observed at the highest dose level in females, therefore it was not considered to be substance-related. The decrease in the alkaline phosphatase level in females in the 500 mg/kg bw/day group was deemed to be incidental and not substance-related.
- 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):
- In females administered 1000 mg/kg bw/day, the absolute kidney weight was increased. The relative weight was not affected and the change was seen only in one sex, leading to the conclusion that this effect had no toxicological relevance. The relative heart weight in males administered 500 and 1000 mg/kg bw/day was reduced slightly, but with statistical significance, while the absolute heart weight was increased in the 500 mg/kg bw/day group. The highest male dose group was not affected and no related effects were noted in the histopathological examination. Therefore, this effect was considered of no toxicological relevance. Some statistically significant changes in organ weights of the thyroid, spleen and adrenal glands were noted in males or females in the 100 or 500 mg/kg bw/day groups. As the changes were either absolute or relative weight, only in one sex and not observed in the highest dose level, they were not considered to be treatment-related. No treatment-related changes were noted in the salivary gland, lungs, pancreas or stomach in the satellite animals.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No substance-related effects were observed on organs or tissues during the histopathological examination. The mucosa of the forestomach in control and treated groups showed degenerative changes or signs of inflammation. 2/10 males and 3/10 females in the control groups plus 2/10 females in the 1000 mg/kg bw/day group had (suspected) hyperplasia; and 7/10 control males, 7/10 control females, 5/10 1000 mg/kg bw/day males and 7/10 1000 mg/kg bw/day females showed focal eosinophilic infiltration of the forestomach. These effects were possibly caused by the repeated use of a stomach tube for the dosing by gavage. As humans do not have a forestomach, this effect is not relevant to human exposure.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- Eggs from a parasite were detected in the faeces of 1 female in the high-dose group. No other significant effects were seen on the faeces appearance or amount.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- (analytical purity of test substance not specified; no urine and neurobihavioural examinations)
- Qualifier:
- according to guideline
- Guideline:
- other: 87/302/EWG, Annex, Part B
- Deviations:
- yes
- Remarks:
- analytical purity of test substance not specified; no urine and neurobihavioural examinations
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- analytical purity of test substance not specified; no urine and neurobihavioural examinations
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany.
- Age at study initiation: ca. 40 days
- Weight at study initiation: 143 - 168 g (153.4 g mean body weight)
- Housing: 2-3 animals per Makrolon Type III cage on softwood bedding (ARWI-Center, Essen, Germany).
- Diet: pelleted Altromin 1324, Altromin, Lage, Germany, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 11 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 48-60
- Air changes (per hr): nodata, 80-490 Lux (the cages were rotated weekly in the rack)
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: March 28th, 1989 - April 28th, 1989 - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The application volume was 5 mL/kg bw.
The dosing solutions were prepared daily immediately before application.
The following concentrations were prepared: 100 mg/ kg bw /day: 2%; 500 mg/kg bw/day: 10%, 1000 mg/kg bw/day: 20%
The total number of applications was 23 or 24 (depending on the day of necropsy).
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily, 5 days/week
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Rationale for selecting satellite groups: Additionally 5 male and 5 female animals per dose were dosed with 0 and 1000 mg/kg/day to determine the reversibility of possible compound-related findings (recovery group).
- Post-exposure recovery period in satellite groups: 27 days - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day, 5 days a week for mortality and clinical signs
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at study termination
- Dose groups that were examined: control group and highest dose group
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination
- Anaesthetic used for blood collection: not reported
- Animals fasted: No data
- How many animals: all animals
- Parameters checked: RBC, HCT, MCV, HGB, WBC, PLT, differential blood count (banded neutrophils, segmented neutrophils, lymphocytes, eosinophils, monocytes, basophils, myelocytes).
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination
- Animals fasted: No data
- How many animals: all animals
- Parameters checked: Urea, Creatinine, Sodium, Potassium, Glucose, Calcium, ASAT, ALAT, AP, gamma-GT, Bilirubin, Chloride, total protein, total Cholesterol.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
ORGAN WEIGHTS:
Absolute and relative organ weights were determined for the following:
Brain, testes, heart, liver, spleen, adrenals, kidneys, thymus. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals
HISTOPATHOLOGY: Yes, animals of the control and highest dose group.
Following organs were examined microscopically:
Aorta thoracica, eyes, large and small intestinum, glandular stomach, cerebrum, urinary bladder, skin, heart, testes, pituitary, cerebellum, liver, trachea, lung, maxillary lymph nodes, mesenterial lymph nodes, spleen, epididymides, adrenal, peripheral nerv, kidney, ovaries, pancreas, prostate, vesicular gland, thymus, salivary gland, oesophagus, sceletal muscle, thymus, uterus, stomach, tongue. - Statistics:
- T-tests according to Sachs and Dunnett; steel-test
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No symptoms were noted as compound-related effects.
- 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):
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean water intake of the male groups 2 and 4 showed a slight increase which was not considered to be compound-related.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological 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 observations like hydrometra, hydronephrosis, discolouration of the thymus and one suspicion of hydrocephalus internus were considered to be spontaneous.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Details on results:
- The histological examination of the organs of the recovery group was not performed, because in the main groups no target organ was evaluated.
- 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:
- other:
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Conclusions:
- According to the described study, a daily administration of 2-Ethylhexylstearate up to 1000 mg/kg bodyweight/day for 28 days caused no cumulative-systemic toxicity to rats. The NOAEL was found to be 1000 mg/kg bw/day.
- Executive summary:
2-Ethylhexylstearate was tested for systemic toxicity at repeated doses of 0 (group 1), 100 (group 2), 500 (group 3) and 1000 (group 4) mg/kg body weight/day. The compound was administered daily by gavage over a period of 28 days. 10 male and 10 female rats were used for each dose. In addition to the groups 1 and 4, 5 male and 5 female animals were used to determine the reversibility of possible compound-related findings (recovery group).
All doses applied were tolerated without lethality. No symptoms were noted as compound-related effects. The mean food consumption of all groups was comparable to the control. The mean water intake of the male groups 2 and 4 showed a slight increase which was not considered to be compound-related. The total body weight gain was comparable to control in all male and female test groups. The haematological examinations showed no compound-related effects. The clinical chemistry showed no compound-related effects. The examination of the eyes by slit lamp microscope showed no compound-related effects. The absolute and relative organ weights showed no compound-related effects. The macroscopical examination of the organs displayed no compound-related effects. Some observations like hydrometra, hydronephrosis, discolouration of the thymus and one suspicion of hydrocephalus internus (animal No. 67) were considered to be spontaneous. The histological examination of the organs of all groups displayed no compound-related effects. The histological examination of the organs of the recovery group was not performed, because in the main groups no target organ was evaluated.
Referenceopen allclose all
Individual body weights of females during the pre-mating and lactation period.
Control group |
Day(s) relative to start |
||
|
1 |
8 |
15 |
11 |
196 |
209 |
212 |
12 |
217 |
228 |
243 |
13 |
210 |
220 |
213 |
14 |
217 |
234 |
244 |
15 |
3211 |
215 |
232 |
16 |
195 |
208 |
197 |
17 |
205 |
224 |
239 |
18 |
212 |
238 |
233 |
19 |
224 |
236 |
259 |
20 |
200 |
218 |
214 |
Mean |
209 |
223 |
229 |
SD |
9 |
10 |
19 |
1000 mg/kg bw |
Day(s) relative to start |
||
|
1 |
8 |
15 |
71 |
200 |
210 |
225 |
72 |
210 |
231 |
234 |
73 |
206 |
234 |
247 |
74 |
210 |
222 |
235 |
75 |
194 |
219 |
218 |
76 |
218 |
243 |
223 |
77 |
214 |
230 |
227 |
78 |
222 |
225 |
210 |
79 |
198 |
200 |
201 |
80 |
203 |
223 |
231 |
Mean |
207 |
224 |
225 |
SD |
9 |
12 |
13 |
Control group |
Day(s) relative to littering |
|
|
1 |
4 |
11 |
286 |
309 |
12 |
323 |
330 |
13 |
325 |
311 |
14 |
331 |
327 |
15 |
311 |
322 |
16 |
282 |
302 |
17 |
309 |
327 |
18 |
312 |
328 |
19 |
315 |
331 |
20 |
300 |
329 |
Mean |
309 |
322 |
SD |
16 |
10 |
1000 mg/kg bw |
Day(s) relative to littering |
|
|
1 |
4 |
71 |
270 |
281 |
72 |
339 |
301 |
73 |
289 |
309 |
75 |
289 |
317 |
77 |
253 |
247 |
78 |
280 |
271 |
79 |
290 |
296 |
80 |
293 |
308 |
Mean |
288 |
291 |
SD |
24 |
23 |
Relative food consumption of females between day 1 and 4 of lactation
Control group |
1000 mg/kg bw |
||
|
|
||
11 |
122 |
71 |
115 |
12 |
91 |
72 |
96 |
13 |
105 |
73 |
63 |
14 |
107 |
75 |
110 |
15 |
106 |
77 |
30 |
16 |
121 |
78 |
63 |
17 |
114 |
79 |
98 |
18 |
100 |
80 |
110 |
19 |
101 |
|
|
20 |
126 |
|
|
Mean |
109 |
Mean |
86 |
SD |
11 |
SD |
30 |
Table 1: Data of selected parameters determined in the study for all groups:
Food consumption (g/animal/d), group mean values |
|
|
|
|
||||
week |
group***, sex (m/f) |
|
|
|
|
|
|
|
|
1 m |
2 m |
3 m |
4 m |
1 f |
2 f |
3 f |
4 f |
1 |
18 |
16 |
18 |
18 |
14 |
15 |
14 |
15 |
2 |
19 |
18 |
21** |
22** |
14 |
14 |
15** |
16* |
3 |
22 |
21 |
21 |
21* |
16 |
17 |
15 |
16 |
4 |
17 |
17 |
19 |
19 |
13 |
13 |
13 |
14 |
Water consumption (mL/animal/d), group mean values |
|
|
|
|
||||
week |
group, sex (m/f) |
|
|
|
|
|
|
|
|
1 m |
2 m |
3 m |
4 m |
1 f |
2 f |
3 f |
4 f |
1 |
29 |
25* |
27 |
29 |
27 |
24 |
24 |
24 |
2 |
28 |
25** |
30 |
31* |
28 |
22** |
26 |
27 |
3 |
33 |
29 |
30 |
30 |
32 |
27 |
26* |
25* |
4 |
30 |
25 |
27 |
29 |
29 |
28 |
24* |
24 |
Body weights and weight gain (g) |
|
|
|
|
|
|
||
week |
group, sex (m/f) |
|
|
|
|
|
|
|
|
1 m |
2 m |
3 m |
4 m |
1 f |
2 f |
3 f |
4 f |
0 |
67 |
60* |
64 |
67 |
64 |
63 |
60 |
63 |
1 |
107 |
96** |
105 |
108 |
96 |
96 |
94 |
95 |
2 |
147 |
137 |
147 |
150 |
123 |
124 |
122 |
124 |
3 |
189 |
178 |
191 |
196 |
146 |
147 |
146 |
147 |
4 |
220 |
208 |
227 |
229 |
161 |
162 |
163 |
173 |
gain week 0-4 |
153 |
148 |
163 |
162 |
97 |
99 |
103 |
110 |
Selected haematology and clinical chemistry parameters (week 4) |
|
|
|
|
|
|||
|
group, sex (m/f) |
|
|
|
|
|
|
|
|
1 m |
2 m |
3 m |
4 m |
1 f |
2 f |
3 f |
4 f |
haemoglobin mmol/L |
10.9 |
10.1** |
9.9** |
9.8** |
10.6 |
9.9** |
9.9** |
9.8** |
red blood cell count T/L |
7.2 |
6.9 |
6.6 |
6.8 |
6.9 |
6.4 |
6.0* |
6.5 |
haematokrit l/L |
0.39 |
0.38 |
0.36 |
0.37 |
0.36 |
0.34 |
0.32** |
0.35 |
alkaline phosphatase U/L |
371 |
356 |
390 |
361 |
247 |
211 |
196* |
206 |
inorganic phosphate |
3.1 |
2.9* |
2.7** |
2.8* |
2.6 |
2.4* |
2.4 |
2.5 |
Organ weights after 4 weeks |
|
|
|
|
|
|
||
|
group, sex (m/f) |
|
|
|
|
|
|
|
|
1 m |
2 m |
3 m |
4 m |
1 f |
2 f |
3 f |
4 f |
thyroid absolute (mg) |
25 |
22* |
23 |
23 |
21 |
23 |
19 |
22 |
spleen absolute (g) |
0.57 |
0.59 |
0.63* |
0.63 |
0.46 |
0.45 |
0.46 |
0.46 |
heart absolute (g) |
0.80 |
0.73* |
0.78 |
0.80 |
0.61 |
0.61 |
0.58 |
0.64 |
kidney absolute (g) |
1.66 |
1.58 |
1.73 |
1.80 |
1.19 |
1.22 |
1.19 |
1.28* |
thyroid relative (% of body weight) |
0.010 |
0.010 |
0.009* |
0.009 |
0.013 |
0.014 |
0.011 |
0.013 |
adrenal relative (% of body weight) |
0.025 |
0.025 |
0.024 |
0.025 |
0.046 |
0.044 |
0.039* |
0.045 |
heart relative (% of body weight) |
0.33 |
0.32 |
0.31** |
0.31* |
0.36 |
0.36 |
0.34 |
0.37 |
* level of significance 95% in comparison with control value
** level of significance 99% in comparison with control value
*** 1 = control, 2 = 100 mg/kg bw/day, 3 = 500 mg/kg bw/day, 4 = 1000 mg/kg bw/day
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 300 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available information comprises adequate and reliable (Klimisch score 1-2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
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
Read Across Justification
There are no data on the repeated dose toxicity of Fatty acids, C16-18, isononyl esters (CAS 91031-57-1). The assessment was therefore based on studies conducted with analogue substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).
Repeated dose toxicity, oral, subacute
CAS 59231-34-4
A combined repeated dose toxicity and reproduction/developmental toxicity screening study was performed according to OECD guideline 422 and under GLP conditions (key study, 2013) with Isodecyl oleate (CAS 59231-34-4). 10 rats/sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day once daily for 35 days (males) and up to 56 days (females) via oral gavage. The application started two weeks before mating and ended on the day of or one day before sacrifice. Day of sacrifice was on day 35 for the male rats and on lactation day 3 or shortly thereafter for the female rats. There was no mortality during the study period. No toxicologically relevant clinical signs were observed. A statistically significant decrease in body weight (‑9.4%) and food consumption (‑21.7%) was noted in females at 1000 mg/kg bw/day during lactation. There were no toxicologically relevant effects on water consumption and organ weights. No treatment-related effects were noted on the ophthalmology -, haematology - and clinical biochemistry parameters. The macroscopic examination at autopsy and subsequent histopathological examination did not reveal any treatment-related changes. The NOAEL for systemic toxicity was considered to be 300 mg/kg bw/day for female rats and 1000 mg/kg bw/day for male rats.
CAS 91031-48-0
A 28-day oral repeated dose toxicity study was performed with Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) similar to OECD 407 and under GLP conditions (supporting study, 1992). Ten Sprague-Dawley rats per sex and dose were administered once daily (5 days a week) 0, 100, 500 and 1000 mg/kg bw/day by gavage, for 28 consecutive days. There was no mortality and no toxicologically relevant clinical signs were observed during the study period. No significant differences in body weight, body weight gain, food consumption, water consumption and organ weight were noted between the control group and treatment groups. No treatment-related effects on the ophthalmology-, hematology- and clinical biochemistry parameters were observed. No treatment-related changes were noted during the gross pathology and histopathology examinations. Based on the absence of adverse toxic effects the NOEL for systemic toxicity was 1000 mg/kg bw/day.
CAS 3687-46-5
A 28-day oral repeated dose toxicity study was performed with Decyl oleate (CAS 3687-46-5) similar to OECD 407 (supporting study, 1987). Ten Wistar rats per sex and dose and 5 per sex and dose satellite rats were administered once daily (5 days a week) 0, 100, 500 and 1000 mg/kg bw/day by gavage, for 28 consecutive days. There was no mortality and no toxicologically relevant clinical signs were observed during the study period. No significant differences in body weight, body weight gain, food consumption, water consumption and organ weight were noted between the control group and treatment groups. No treatment-related effects on the ophthalmology-, hematology- and clinical biochemistry parameters were observed. No treatment-related changes were noted during the gross pathology and histopathology examinations. Based on the absence of adverse toxic effects the NOAEL for systemic toxicity was 1000 mg/kg bw/day.
Overall conclusion for repeated dose toxicity
The data for the source substance showed no toxicologically relevant effects up to and including the recommended limit values. Therefore, as the available data did not identify any hazard for repeated dose toxicity, Fatty acids, C16-18, isononyl esters (CAS 91031-57-1) is not considered to be hazardous following repeated exposure.
In order to fulfil the standard information requirements according to Regulation (EC) No. 1907/2006, Annex IX, Column 1, Section 8.6.2, a GLP-compliant oral subchronic toxicity study following OECD guideline 408 is proposed. Column 2 adaption possibilities at the Annex IX level where considered and do not apply. In addition, the general adaptation possibilities of Annex XI of the REACH Regulation are not adequate to generate the necessary information.
Justification for classification or non-classification
According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to Fatty acids, C16-18, isononyl esters (CAS 91031-57-1), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.
Therefore, based on the analogue read-across approach, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.