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EC number: 800-884-5 | CAS number: 1154308-86-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- 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:
- 24 Sep 2012 to 30 Jan 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Compliant with current guidelines and GLP compliant.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- N-(2-hydroxyethyl)-3,5,5-trimethylhexanamide
- EC Number:
- 800-884-5
- Cas Number:
- 1154308-86-7
- Molecular formula:
- C11 H23 N1 O2
- IUPAC Name:
- N-(2-hydroxyethyl)-3,5,5-trimethylhexanamide
- Details on test material:
- - Name of test material (as cited in study report): Additol® SXW 6246/90 Coating Additives
- Physical state: Amber Liquid
- Analytical purity: 94.67% (+5.33% water)
- Batch no.: 210129777
- Expiration date of Batch no. 210129777: 28 February 2013
- Storage condition of test material: Ambient, Dark
- Composition of test material, percentage of components: Amides, C8-12, N-(hydroxyethyl) 90622-90-5 (94.67%) and Water 7732-18-5 (5.33%)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 8-9 weeks
- Weight at study initiation: Males: 303-372g: Females: 215-265g
- Fasting period before study: None
- Housing: 2 or 3 per sex per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23C
- Humidity (%): 40-70%
- Air changes (per hr): Minimum of 10
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light
IN-LIFE DATES: From: 24 Sep 2012 To: 16 Nov 2013
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test item is miscible with corn oil but not with water or other vehicles.
- Concentration in vehicle: 10-100 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): Not applicable
- Purity: Not applicable - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Achieved concentration and homogeneity determined to be within acceptance criteria at Weeks 1 and 4 of study.
- Duration of treatment / exposure:
- Once daily oral gavage adminsitration as follows:
Males: 28 days
Females: between 42 and 46 days (dependent upon dates of mating and parturition) - Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Doses: 0, 30, 75 and 125 mg/kg/day
Basis:
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:The dose levels were agreed with the Sponsor following evaluation of existing relevant toxicological data, including a 7-day dose range finding study (Charles River Study No. 496177).
- Rationale for animal assignment (if not random): Not applicable- random allocation
- Rationale for selecting satellite groups: Not applicable
- Post-exposure recovery period in satellite groups: Not applicable
- Section schedule rationale (if not random): Not applicable - Positive control:
- Not applicable
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals checked hourly up to 4 hours post dose on each day of dosing
- Cage side observations: Twice daily mortaility checks (am/pm)
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Once during pre-trial and then daily throughout the treatment period.
FOOD CONSUMPTION
- Food consumption: Weekly prior to pairing for mating. No further food consumption for the males, however food consumption measured for females on Days 0-7, 7-14 and 14-20 of gestation and 0-4 of lactation.
WATER CONSUMPTION Yes
- Time schedule for examinations: Water consumption was monitored regularly by visual inspection of water bottles however no data was recorded.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pre-trial, Week 4 (males) and prior to sacrifice (females in early lactation).
- Dose groups that were examined: All
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 4 (males), ~ Day 4 of lactation (females)
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: 5 animals per sex per dose group
- Parameters examined:
Red blood cell count
Haemoglobin
Haematocrit
Mean cell volume
Red blood cell distribution width
Mean cell haemoglobin concentration
Mean cell haemoglobin
Reticulocyte count
Platelet count
White blood cell count
Neutrophil count
Lymphocyte count
Monocyte count
Eosinophil count
Basophil count
Large unclassified cells
Activated partial thromboplastin time
Fibrinogen
Prothrombin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 4 (males), ~ Day 4 of lactation (females)
- Animals fasted: No
- How many animals: 5 animals per sex per dose group
- Parameters examined:
Urea
Glucose
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
Creatine phosphokinase
Lactate dehydrogenase
Sodium
Potassium
Chloride
Total protein
Albumin
Globulin
Albumin/globulin ratio
Cholesterol
Creatinine
Total bilirubin
Calcium
Phosphate
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Weekly
- Dose groups that were examined: All
- Battery of functions tested:
Cageside and standardised arena observations (Weekly)
Grip strength, pain perception, landing foot splay and motor activity (Males (all): Week 4: Females (5 animals per group): Day 3 of lactation) - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- Reproductive endpoints included in separate IUCLID summary.
- Statistics:
- Where required to assist with interpretation, tests were applied to determine the statistical significance of observed differences between Control and groups receiving test item. All statistical tests were two-sided and performed at the 5% significance level using in house software. Pairwise comparisons were only performed against the control group.
Body weight and food consumption (prior to mating), haematology, coagulation, clinical chemistry and selected FOB and motor activity data was analysed for homogeneity of variance using the ‘F Max' test. If the group variances appeared homogeneous, a parametric ANOVA was used and pairwise comparisons were made using Fisher’s F protected LSD method via Student's t test ie pairwise comparisons were made only if the overall F test was significant. If the variances were heterogeneous, log or square root transformations were used in an attempt to stabilise the variances. If the variances remained heterogeneous, then a Kruskal-Wallis non-parametric ANOVA was used and pairwise comparisons were made using chi squared protection (via z tests, the non-parametric equivalent of Student's t test).
Organ weight data was analysed as above, and by analysis of covariance (ANCOVA) using terminal body weight as the covariate.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- 9 female animals were found dead/prematurely euthanised either in late gestation/early lactation; the distribution had no assocaiation to dose level and they were not considered test-item related. Excess salivation noted post dose in test animals.
- Mortality:
- no mortality observed
- Description (incidence):
- 9 female animals were found dead/prematurely euthanised either in late gestation/early lactation; the distribution had no assocaiation to dose level and they were not considered test-item related. Excess salivation noted post dose in test animals.
- 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 specified
- Description (incidence and severity):
- No inter-group differences were noted during the study, however there was no positive data recorded
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean liver weights were higher than Control in males at all dose levels and slightly higer at 75 and 125 mg/kg/day in females. Mean kidney weights were higher than Control in males at all dose levels (no effects in females).
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Liver: centrilobular hypertrophy (males and females at 125 mg/kg/day: only dose level examined). Kidneys (males at 125 mg/kg/day only): intraepithelial hyaline droplets, single cell necrosis, foci of basophilic (regenerating) tubules, granular casts.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Mortaility:
There were 9 female animals found dead or prematurely euthanised either in late gestation or early lactation (between Day 22 of gestation and Day 2 of lactation). Although a definitive cause of death could not be established for many of these animals, the distribution of the deaths; 2/10, 4/10, 1/10 and 2/10 (0, 30, 75 and 125 mg/kg/day, respectively) indicated that they were not related to the test item.
Clincal Signs:
Excess salivation was noted post dose in animals receiving the test item. This sign was transient and was considered not to be adverse.
Organ Weights:
Absolute mean liver weights were higher than Control in males at all dose levels (1.11X, 1.06X and 1.13X Control mean, at 30, 75 and 125 mg/kg/day, respectively. In females, absolute mean liver weights were slightly higher than Control at 75 and 125 mg/kg/day (1.06X and 1.08X Control mean, respectively).
Absolute mean kidney weights were higher than Control in males at all dose levels (1.08X, 1.08X and 1.19X Control mean, at 30, 75 and 125 mg/kg/day, respectively). There were no clear differences between the kidney weights of females receiving the test item and Control females.
Histopathology:
In the liver minimal or mild centrilobular hypertrophy of hepatocytes was present in 4/5 males and 5/5 females at 125 mg/kg/day.
In comparison to Control there was a moderate or marked increase in intraepithelial hyaline droplets in the cortical tubules in the kidneys of males at125 mg/kg/day. Associated with the droplets were minimal single cell necrosis of the tubular epithelium, an increase in the incidence and severity of foci of basophilic (regenerating) tubules and, in 2/5 animals, granular casts at the cortico-medullary junction. These findings were considered to be consistent with a diagnosis of ‘hyaline-droplet nephropathy’ caused by an overload of the male rat specific protein alpha-2-microglobulin.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 125 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects considered adverse or relevant to humans were observed after 28 or more days of exposure. The highest dose administered was established as the NOAEL
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, and based on the lack of human relevance of findings in the male kidneys at the high dose, the systemic or parental NOAEL was considered to be 125 mg/kg bw/day.
- Executive summary:
A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was conducted to determine the toxicity to reproduction and/or development of test substance, according to OECD Guideline 422, in compliance with GLP. Sprague-Dawley rats were randomised into 3 test groups and one Control group, each containing 10 males and 10 females. Males were treated by oral gavage at doses from 30, 75 and 125 mg/kg bw/day for 2 weeks prior to mating, then through mating, until the day prior to necropsy (4 weeks of treatment). Females were treated with the same doses for 2 weeks prior to mating, then through mating, gestation and until at least Day 4 of lactation (ca. 6 weeks of treatment). The following parameters and end points were evaluated in this study: clinical signs, body weights, food consumption, ophthalmology, detailed functional tests and observations, reproductive parameters (mating and pregnancy performance, fertility, maternal care and pup performance), clinical pathology parameters (haematology, coagulation and clinical chemistry), organ weights, and gross and microscopic pathological examinations. There were no test substance related effects on body weights, body weight changes, food consumption, ophthalmology, detailed functional tests and observations, clinical pathology parameters (haematology, coagulation and clinical chemistry) or gross necropsy findings. Excess salivation noted transiently post dose in animals receiving the test substance may have been a consequence of an unpleasant taste associated the test substance; it was nevertheless considered not to be adverse. The distribution of the 9 female animals found dead or prematurely euthanised (2/10, 4/10, 1/10 and 2/10 at 0, 30, 75 and 125 mg/kg bw/day, respectively) either in late gestation or early lactation (between Day 22 of gestation and Day 2 of lactation) indicated no clear relationship to the test substance. Furthermore, these animals were not observed to be suffering from clinical signs that were considered to be test substance-related; indeed other than the salivation noted above, there were no clinical signs in the animals surviving to the end of the study that were considered to be test substance related. Similarly, test substance related histopathological findings were not observed to a greater degree/severity in the premature decedents relative to the animals surviving to terminal sacrifice. There were no test substance-related effects on mating, pregnancy performance, fertility or maternal care and pup performance (litter survival and pup weights). It should be noted that there were high absolute numbers of litter losses (2/8, 2/6, 1/9 and 3/9 of surviving females at 0, 30, 75 and 125 mg/kg bw/day, respectively) and low viability rates (66%, 74%, 87% and 63% at 0, 30, 75 and 125 mg/kg bw/day, respectively); however the distribution of these findings indicated no clear relationship to the test substance. The minimal or mild centrilobular hypertrophy of hepatocytes in the livers of animals at 125 mg/kg bw/day, correlated with high liver weights in animals receiving the test substance. Whilst this finding was considered to be test substance related, it was not associated with any changes in clinical chemistry parameters and was considered to be an adaptive response and not adverse. The histopathological findings in the kidneys of males at 125 mg/kg bw/day were consistent with a diagnosis of ‘hyaline-droplet nephropathy’, which correlated with high kidney weights in males receiving the test substance. The findings were considered to be caused by an accumulation of complexes of the male rat specific protein alpha-2-microgloblin and the test substance that were resistant to degradation. As little or no alpha-2-microgloblin protein is present in man, Greaves (2007), these findings were considered not to be relevant to man. Therefore, under the conditions of this study, and based on the lack of human relevance of findings, the parental, reproductive and neonatal NOAEL was considered to be 125 mg/kg bw/day (Wallace, 2013).
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