Registration Dossier
Registration Dossier
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EC number: 203-372-4 | CAS number: 106-20-7
- 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
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- other: dose-range finder
Reference
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods
- Principles of method if other than guideline:
- The purpose of this study was to determine dose levels of Di-(2-ethylhexyl)amine suitable for use in a subsequent Reproduction/Developmental Toxicity Screening Test in the Han Wistar Rat.Groups of 4 male and female rats were treated by gavage for 14 days.
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Laboratories, B.V.
- Age at study initiation: 11 weeks
- Weight at study initiation: Males: 269 - 364g, females: 203-236g
- Housing: individually
- Diet (e.g. ad libitum): ad lib. (Harlan Teklad 2018C (batch no. 80/11))
- Water (e.g. ad libitum): ad lib.
- Acclimation period: >= 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
daily, homogeneity was maintained by constant stirring
VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- all results were within 97 and 106.5% of the target concentration. Homogeneity differences were below 15%. Formulations were found to be stable when stored for 8 days at room temperature (maximum derivation: 1.6%)
- Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- daily
- Dose / conc.:
- 30 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 4
- Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: daily
FOOD CONSUMPTION
- Food consumption: recorded at weekly intervals per animal
OPHTHALMOSCOPIC EXAMINATION: No
BLOOD COLLECTION
- Time schedule for collection of blood: end of treatment
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (18h, water available ad lib.)
- How many animals: all (except high dose due to excessive mortality)
HAEMATOLOGY: Yes
Erythrocyte count
Hemoglobin
Hematocrit
Mean corpuscular volume
Red cell volume distribution width
Mean corpuscular hemoglobin
Protrhombin time
Activated partial Thromboplastin time
CLINICAL CHEMISTRY: Yes
Glucose
Urea
Creatinine
Bilirubin, total
Cholesterol, total
Triglycerides
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
Gamma-glutamyl-transferase
Bile acids - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Livers, kidneys, adrenals, spleen, and all macroscopic changes were preserved in neutral phosphate buffered 4% formaldehyde solution for possible microscopic examination
The organ weights were determined for Adrenal glands (weighed as pairs), Kidneys (weighed as pairs), Liver, Spleen
HISTOPATHOLOGY: No - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical signs observed at 300 mg/kg bw./day included salivation, bedding in mouth, decreased activity, ruffled fur, hunched posture, diarrhea, stiff gait, and reddish nasal secretion. Visible body weight loss and vocalization on touch was observed in one female. All these findings were considered to be test item-related.
Salivation and bedding in mouth were observed in males and females at 100 mg/kg bw./day. One male showed chromodacryorrhea.
At a dose level of 30 mg/kg bw/day, no clinical signs were recorded. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- At a dose level of 300 mg/kg bw/day, male no. 9 and female no. 21 died spontaneously on day 9 or 8, respectively, and two females (nos. 22 and 24) were killed in extremis on day 8 of the treatment period. Due to the high mortality, dosing of the remaining animals was stopped on day 9 of the treatment period and these animals were sacrificed on day 10. The increased mortality was considered to be test item-related.
At a dose level of 30 and 100 mg/kg bw/day, all animals survived until planned necropsy. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At a dose level of 300 mg/kg bw/day, for males and females mean body weight gain was reduced after treatment start and after approximately one week a body weight loss was observed.
At a dose level of 100 mg/kg bw/day, mean body weight gain was reduced (statistically significant towards the end of the treatment period) during the whole treatment period (5% and -6% in males and females compared to 11% and 2% in the control group, respectively), resulting in slightly reduced mean body weights.
At a dose level of 30 mg/kg bw/day, mean body weight gain was similar to the control group. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- At a dose level of 300 mg/kg bw/day, mean food consumption was reduced by approximately 40% in males and females during treatment.
At a dose level of 100 mg/kg bw/day, mean food consumption was reduced by 12% (not statistically significantly) in males but increased by 4% in females during treatment.
At a dose level of 30 mg/kg bw/day, mean food consumption was slightly reduced (in males statistically significantly) during treatment. Since lower mean food consumption was already observed in the acclimatization period for this added dose group, this finding was considered to be a result of biological variability. - Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- At 100 mg/kg bw/day in females, absolute and relative liver weights were slightly increased (+14% for relative liver weights compared to the control group).
No other alterations were noted. No organ weights have been assessed for the 300mg/kg group due to early euthanization. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At 300 mg/kg bw/day, male no. 9, which died spontaneously, had a distended stomach, liquid in the gut and enlarged adrenal glands. Also the three females (nos. 21, 22 and 24), which died spontaneously or were killed in extremis, had enlarged adrenal glands.
No other test item-related findings were noted at any dose level. - Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Conclusions:
- High dose animals showed body weight loss, diarrhea, and signs of pain and extreme discomfort, e.g., salivation, bedding in mouth, hunched posture, and vocalization, which are all attributed to the caustic properties of test substance. Animals receiving 100mg/kg still showed salivation and bedding in mouth. Since the mid dose also gained significantly less weight than the controls, this dose was deemed too high for the longer study duration of an OECD 422 and the use of pregnant females. The only systemic effect observed was an increase in liver weight and cholesterol, which is seen as a sign of metabolism of the substance and adaptive, but non-adverse. This view is supported by the absence of evidence for impaired liver function in the extensive examinations of the OECD 422 study. Based on these observations, dose levels of 7.5, 25 and 75 mg/kg bw/day were selected for the subsequent Reproduction/Developmental Toxicity Screening Test in the Han Wistar Rat.
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:
- Bis(2-ethylhexyl)amine
- EC Number:
- 203-372-4
- EC Name:
- Bis(2-ethylhexyl)amine
- Cas Number:
- 106-20-7
- Molecular formula:
- C16H35N
- IUPAC Name:
- bis(2-ethylhexyl)amine
- Details on test material:
- - Name of test material (as cited in study report): Di-(2-ethylhexyl)amine
- Physical state: Colourless, clear liquid
- Analytical purity: 98.5 g/100 g
- Lot/batch No.: 000STD77L0
- BASF test substance number: 11/0454-1
- Expiration date of the lot/batch: 11.11.2013
- Stability of Test Item in Vehicle: 8 days at room temperature
- Storage condition of test material: Room temperature (20 ± 5 °C)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Laboratories, B.V., NM Horst / Netherlands
- Age at study initiation: 11 weeks
- Weight at study initiation: Males: 293 to 336 g, Females: 205 to 250 g
- Housing: In groups of five or six in Makrolon type-4 cages with wire mesh tops up to the day of randomization and afterwards individually in Makrolon type-3 cages with wire mesh tops and sterilized standard softwood bedding with paper enrichment. During the pre-pairing period, cages with males were interspersed amongst those holding females to promote the development of regular estrus cycles.
- Diet: Pelleted standard Harlan Teklad 2018C rodent maintenance diet (Provimi Kliba SA, Kaiseraugst/Switzerland) was available ad libitum.
- Water: Community tap-water from Fuellinsdorf was available ad libitum in water bottles.
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The dose formulations were prepared weekly. Di-(2-ethylhexyl)amine was weighed into a glass beaker on a tared precision balance and the vehicle was added (w/v). Using an appropriate homogenizer, a homogeneous suspension was prepared. Separate formulations were prepared for each concentration. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- On the first treatment day samples from the control group (middle only) as well as three samples (top, middle and bottom) of about 0.5 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. Samples of about 0.5 g of each concentration were taken from the middle to confirm the stability. On 16-Aug-2012, samples were taken from the middle to confirm concentration. The samples were analyzed by GC coupled to an FID detector following an analytical procedure provided by the Sponsor and adapted at Harlan Laboratories. The test item was used as the analytical standard. Duplicates were taken of all samples. The results indicate the accurate use of the test item di-(2-ethylhexyl)amine and corn oil as vehicle during this study. Application formulations were found to be homogeneously prepared and sufficient formulation stability under storage conditions was approved.
- Duration of treatment / exposure:
- - Males: minimum 4 weeks;
- Females: approximately 6 weeks;
Males were sacrificed after treatment of 28 days, when no longer needed for the assessment of reproductive effects. Pups were sacrificed on day 4 post partum. Dams were sacrificed on day 5 post partum. Since in several females a birth did not occur on the expected date (day 21 post coitum), these dams were sacrificed on day 25 post coitum. - Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 7.5 mg/kg bw/day (nominal)
- Remarks:
- nominal conc. in vehicle
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 11
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: In a 14-day dose range-finding study (D52701, BASF project number 01R0454/11X312), four rats per group were exposed by gavage to 30, 100, or 300mg/kg b.w. bis(2-ethylhexyl)amine. All high dose animals died or were euthanized by day 10. These animals showed body weight loss, diarrhea, and signs of pain and extreme discomfort, e.g., salivation, bedding in mouth, hunched posture, and vocalization, which were all attributed to the caustic properties of test substance. Animals receiving 100mg/kg still showed salivation and bedding in mouth. Since the mid dose also gained significantly less weight than the controls, this dose was deemed too high for the longer study duration of an OECD 422 and the use of pregnant females.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Viability / Mortality: twice daily; Clinical signs: once daily, during acclimatization and up to day of necropsy; additionally females were observed for signs of difficult or prolonged parturition, and behavioral abnormalities in nesting and nursing;
- Cage side observations: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern); changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies or bizarre behavior;
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once prior to the first administration of the test item (day 6 of acclimatization) and weekly thereafter (in the gestation period on day 0, 6, 13 and 20 post coitum), detailed clinical observations were performed outside the home cage in a standard arena;
BODY WEIGHT: Yes
- Time schedule for examinations: daily (from treatment start to day of necropsy)
FOOD CONSUMPTION AND COMPOUND INTAKE: Males: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 - 14; after pairing period days 1 - 8 and 8 - 11; Females: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 - 14; gestation days 0 – 7, 7 - 14 and 14 – 21 and days 1 - 4 of the lactation; no food consumption was recorded during the pairing period;
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of the scheduled necropsy (males); on day 5 post partum (females);
- Anaesthetic used for blood collection: Yes (light isoflurane anesthesia)
- Animals fasted: Yes
- How many animals: 5 males randomly selected from each group, 5 lactating females from each group;
- Parameters checked: Erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, red cell volume distribution width, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin concentration distribution width, leukocyte count (total), differential leukocyte count, platelet count, reticulocytes, prothrombin time (= Thromboplastin time), activated partial thromboplastin time;
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of the scheduled necropsy (males); on day 5 post partum (females);
- Animals fasted: Yes
- How many animals: 5 males randomly selected from each group, 5 lactating females from each group;
- Parameters checked: Glucose, urea, creatinine, bilirubin (total), cholesterol (total), triglycerides, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl-transferase, bile acids, sodium, potassium, chloride, calcium, phosphorus, protein (total), albumin, globulin, albumin / globulin ratio
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: at one time during the study (males two days before the scheduled sacrifice and females on day 3 post partum) following the daily dose administration;
- Dose groups that were examined: five P generation males and five P generation females randomly selected from each group;
- Battery of functions tested: Cage-side observations (faeces-balls, urine and posture as well as resistance to removal), hand-held observations (muscle tone, constitution, skin, pupil size, palpebral closure, lacrimation, salivation, reaction to handling and general abnormalities), open field observations (level of ambulatory activity including rearing (one minute evaluation), unusual body movements (e.g. spasms, convulsions), gait evaluation, behavior, hair coat, respiration, quantity of faeces-balls and urine), reflexes (blinking, palpebral closure, pinna reflex, extensor thrust response, paw pinch,
responsiveness to sharp noise, righting reflex and hearing ability (Preyer’s reflex)), measurements / counts (hind limb / fore limb grip strength, rectal temperature); additionally, locomotor activity was measured quantitatively for the same animals (with an Activity Monitor AMS-0151 (FMI, Germany); activity of the animals (based on beam count) was recorded for 6-minute intervals over a period of 30 minutes);
OTHER: Furthermore, an additional blood sample (0.5 mL) was collected into serum tubes for possible future measurement of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). Serum samples were stored at ≤ -75°C. Any samples remaining at finalization of the study report were discarded. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
(For the parent animals, special attention was directed at the organs of the reproductive system.)
HISTOPATHOLOGY: Yes
(all gross lesions, testes, epididymides, prostate, seminal vesicles, ovaries, oviduct, vagina and uterus from all animals of the control and high-dose group, the remaining organs/tissues of 5 randomly selected males and females of the control and high-dose group, respectively, were examined histopathologically; special emphasis was made on the stages of spermatogenesis and histopathology of interstitial cell structure; histological examination of ovaries was carried out on the females that did not give birth; in addition, microscopic examination of the reproductive organs of all infertile males was made;)
Organ weights:
- all parental males: testes and epididymides (of all parental males);
- from 5 males and 5 females killed at the end of the study which were selected for hematology and clinical chemistry examination from each group: adrenal glands (weighed as pairs), brain, heart, kidneys (weighed as pairs), uterus (including cervix), prostate, liver, thymus, spleen, thyroid (after fixation), ovaries (weighed as pairs), seminal vesicles (inclusive coagulating gland);
Tissue preservation:
- all parental males: prostate, seminal vesicles with coagulating gland, testes (in Bouin’s fixative), epididymides (in Bouin’s fixative);
- all parental females: ovaries (with oviduct), uterus (with vagina);
- all males and females: gross lesions, brain, spinal chord (cervical, thoracic, lumbar), small and large intestines (incl. Peyer’s patches), stomach (forestomach and glandular stomach), liver, kidneys, adrenals, lymph nodes (axillary and mesenteric), urinary bladder, heart, thymus, thyroids and parathyroids, trachea and lungs, spleen, peripheral nerve (sciatic), bone marrow (femur);
- all males and females (only examined by histopathology in case of macroscopic findings indicative of potential toxicity): aorta, eyes with optic nerve and harderian gland, lacrimal gland, larynx, nasal cavity, esophagus, pituitary gland, femur with knee joint, mammary gland (male and female), pancreas, salivary glands – mandibular, sublingual, skeletal muscle, sternum with bone marrow, pharynx; - Statistics:
- - food consumption, body and organ weights, clinical laboratory and reproduction data and macroscopical findings: means and standard deviations of various data were calculated; the Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex; the Steel-test (many-one rank test) was applied instead of the
Dunnett-test when the data could not be assumed to follow a normal distribution; Fisher's exact-test was applied if the variables could be dichotomized without loss of information;
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs were noted in controls or in animals treated at 7.5 and 25 mg/kg bw/day. At 75 mg/kg bw/day in males and females, bedding in mouth were observed from the end of the pre-pairing period or pairing period onwards until one day before necropsy. This was accompanied by slight salivation in some animals. This was considered to be a sign of discomfort and without toxicological relevance. No findings were noted at detailed weekly clinical observation.
- Mortality:
- no mortality observed
- Description (incidence):
- There were no unplanned deaths during the whole course of the study.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- No test item-related effects on mean body weights and mean body weight gain were noted in males at 7.5 and 25 mg/kg bw/day. At 75 mg/kg bw/day, there was a slight decrease in mean body weight gain after treatment start during the first week of the pre-pairing period (23 g compared to 28 g in the control group). Afterwards no decrease was observed anymore. This slight effect could be test item-related but was considered to be not adverse. The overall differences in mean body weight gain at the dose levels of 0, 7.5, 25 and 75 mg/kg bw/day were: +17%, +15%, +17% and +16% during the pre-pairing period and +3%, +2%, +3% and +2% during the after pairing period (percentages refer to the body weight gain within the period). No test item-related effects on mean body weight and mean body weight gain were noted in females. The overall differences in mean body weight gain at the dose levels of 0, 7.5, 25 and 75 mg/kg bw/day were: +7%, +8%, +8% and +7% during the pre-pairing period, +50%, +52%, +53% and +50% during the gestation period and +5%, +3%, +6% and +4% during the lactation period (percentages refer to the body weight gain within the period).
- Description (incidence and severity):
- No test item-related effects on mean food consumption were noted in males and females.
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The assessment of the hematology data did not reveal any test item-related effects in males and females. Statistically significant differences (lower hemoglobin, MCHC, and eosinophil values in females at 7.5 mg/kg bw/day; lower eosinophil values in females and higher RDW levels in males at 25 mg/kg bw/day; higher HDW values in females at 75 mg/kg bw/day) showed either no dose-dependency or the values were in the range of the historical control data.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The assessment of the clinical biochemistry data did not reveal any test item-related effects in males and females. At 75 mg/kg bw/day, there was an increase in triglycerides and a decrease of total bilirubin in males and an increase in total cholesterol in females. The values of total bilirubin were within the historical control data. The alterations of triglycerides and cholesterol were considered to be of no toxicological relevance, since the differences to the control group were minor and were evident in one sex only. The same applies to the significantly higher ALP activities in females at 7.5 mg/kg bw/day, since there was no dose-dependency.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No test item-related findings were noted during the functional observational battery in males and females at any dose level. One female treated at 7.5 mg/kg bw/day showed increased rearings. At 75 mg/kg bw/day, one female vocalized spontaneously when held in the hand. These isolated findings were considered to be incidental. Another female at 75 mg/kg bw/day showed salivation, which was already noted and discussed at the daily clinical investigation. The body temperature in males treated at 25 and 75 mg/kg bw/day was statistically significantly decreased (38.1°C and 37.6°C, respectively, compared to 38.6°C in the control group). Since these values were within the range of the historical control data (37.5 - 38.6°C), this finding was considered to be not test item-related. No such trend towards lower body temperatures was noted in females. Locomotor activity was not affected by the treatment with the test item in males or females at any dose level.
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- In males, no effects on organ weights were noted. In females, a dose-dependent and statistically significant increase in liver and kidney weight as well as liver and kidney to body and to organ weight ratio were noted at 25 and 75 mg/kg bw/day. This was considered compound-related, but not adverse, since there was no evidence for an impaired organ function by clinical chemistry, macroscopic examinations at necropsy and histopathology.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no gross lesions that could be attributed to treatment with the test item. All gross lesions recorded were considered to be within the range of normal background alterations. In males, incidental findings were a reddish or dark red discoloration of the pancreas and a yellowish and firm nodule in the pancreas. Additionally, two males showed following findings in the testes: at 25 mg/kg bw/day a hardening on the right side was noted, and at 75 mg/kg bw/day a reduction in size was present. However, those two males mated successfully. At microscopic examination of those two animals, the left testis of the male treated at 25 mg/kg bw/day was normal. In the male treated at 75 mg/kg bw/day, a moderate bilateral tubular degeneration/atrophy was noted at microscopic examination. Due to the low incidence and the lack of dose-dependency all these findings were considered to be incidental. In females, the most frequently incidental findings were a reddish or dark red discoloration of the ovaries and foci on or a reduction in size of the thymus, which was present in all dose levels without dose-dependency.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All microscopic findings recorded were within the range of normal background lesions which may be recorded in animals of this strain and age.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Effect levels
- Dose descriptor:
- NOAEL
- Remarks:
- (systemic)
- Effect level:
- 75 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be 75 mg/kg body weight/day, because no adverse effects were observed.
- Executive summary:
The purpose of this OECD 422 study was to generate preliminary information on the possible health hazards likely to arise from repeated exposure to Bis(2 -ethylhexyl)amine. In addition, it provided information on possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus and parturition.
Di-(2-ethylhexyl)amine was administered to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.
The following dose levels were applied: 0 (control group), 7.5, 25, or 75 mg/kg body weight/day.
A standard dose volume of 4 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (corn oil).
The following results were obtained:
Parent animals
- General Tolerability: There were no unplanned deaths during the course of this study. Clinical signs were limited to animals treated at 75 mg/kg bw/day and consisted of bedding in mouth, accompanied by slight salivation in some isolated animals. This was considered to be a sign of discomfort and without toxicological relevance.
- Food consumption: No effects on food consumption of males and females were observed at any dose level.
- Body weights: At 75 mg/kg bw/day, there was a slight decrease in mean body weight gain after treatment start (23 g compared to 28 g in the control group). This slight effect could be test item-related but was
considered to be not adverse. In females no effects on mean body weight and mean body weight gain were noted.
- Clinical laboratory investigations: The assessment of the hematology and clinical biochemistry data did not reveal any test item related effects in males and females.
- Reproduction and breeding data: Mean precoital time, fertility index and conception rate were not affected by the treatment with the test item. Mean number of litter size was similar in all groups and no effects on postnatal loss were observed at any dose level.
- Organ weights: Liver and kidney weights were increased in females at 25 and 75 mg/kg bw/day. These findings were considered compound-related, but not adverse, since there was no evidence for an impaired organ function by clinical chemistry and histopathology.
- Macroscopical findings and histopathological examinations: There were no test item-related findings noted at necropsy. All microscopic findings recorded were within the range of normal background lesions which may be recorded in animals of this strain and age.
Litter data - F1 pups
- Findings at First Litter Check and during Lactation: No test item-related external findings were noted at first litter check.
- Pup Weights to Day 4 Post Partum: No effects on pup weight and pup weight gain were observed.
- Macroscopical Findings: At necropsy of pups, there were no abnormal findings.
Conclusion
The general NOAEL (No Observed Adverse Effect Level) was considered to be 75 mg/kg body weight/day.
The NOEL (No Observed Effect Level) for reproduction/developmental toxicity was considered to be 75 mg/kg body weight /day.
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