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EC number: 239-816-9 | CAS number: 15721-78-5
- 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
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 26 January 2015 to Febuary 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- see results
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- - CAS RN: CAS RN 15721-78-5
- Physical State/Appearance: Off white powder
- Purity: 93.2%
- Batch Number: HY14KSV07
- Date Received: 11 October 2015 - Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Male and female Wistar Han™:RccHan™:WIST strain rats were used
- Eighty animals (forty males and forty females) were accepted into the study
- The animals were acclimatized for nine days
- At the start of treatment animals were approximately six to eight weeks old; the males weighed 190 to 239 g, the females weighed 147 to 183 g (all weighing within ±20% of the mean weight for either sex)
- Housed in groups of three or four by sex
- Solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding
- Free access to food and water
- Pelleted diet rodent feed
- Tap drinking water was supplied from polycarbonate bottles attached to the cage.
- Environmental enrichment: wooden chew blocks; cardboard fun tunnels
- The animals were housed in a single air-conditioned room within the laboratory
- Rate of air exchange was at least fifteen air changes per hour
- 12 hours continuous light and 12 hours darkness
- Environmental conditions were continuously monitored by a computerized system; target ranges for temperature and relative humidity were 22 ± 3 °C and 50 ± 20% respectively; there were no deviations from these targets
- The animals were randomly allocated to treatment groups using a stratified body weight randomization procedure and the group mean body weights were then determined to ensure similarity between the treatment groups
- Cage distribution within the holding rack was also randomized
- Animals were uniquely identified by an ear punching system
Schedule
Experimental Starting Date: 26 January 2015
Experimental Completion Date: 16 July 2015
In-Life Phase: 20 February 2015 to 22 May 2015 - Route of administration:
- oral: gavage
- Details on route of administration:
- Wistar Han™:RccHan™:WIST
- Vehicle:
- arachis oil
- Details on oral exposure:
- The test item was prepared at the appropriate concentrations as a suspension in Arachis oil BP, by gavage using a stainless steel cannula attached to a graduated, disposable plastic syringe.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability and homogeneity of the test item formulations were determined by Envigo Research Limited, Shardlow, UK, Analytical Services. Results show the formulations spanning the concentration ranges used in this study to be homogenously prepared and stable for up to twenty-five days when stored refrigerated (approximately 4°C) in the dark. Formulations were therefore prepared and used within the stability period, divided into daily aliquots and stored at approximately 4 ºC, in the dark, prior to use.
Samples of each test item formulation were collected and analyzed for concentration of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine (CAS RN 15721-78-5) at Envigo Research Limited, Shardlow, UK, Analytical Services. The results indicate that the prepared formulations were within 95% to 105% of the nominal concentration and, thus, within the specified ±10% of the nominal content. - Frequency of treatment:
- The test item was administered once daily, for 90 consecutive days.
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 animals per sex per dose.
- Control animals:
- yes
- yes, concurrent vehicle
- Details on study design:
- The volume of test and control item administered to each animal was based on the most recent scheduled body weight and was adjusted at weekly intervals.
- Observations and examinations performed and frequency:
- Clinical signs, functional observations, body weight change, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Ophthalmoscopic examination was also performed on animals from all dose groups before the start of dosing and on control group and high dose animals during Week 12 of the treatment period.
- Sacrifice and pathology:
- All animals were subjected to gross necropsy examination, and histopathological evaluation of selected tissues from high dose and control animals was performed.
- Statistics:
- Statistical analysis was performed on the following parameters:
- Grip Strength, Motor Activity, Body Weight Change, Hematology, Blood Chemistry, Absolute Organ Weights, Body Weight-Relative Organ Weights.
- Data were analyzed using the decision tree from the ProvantisTM Tables and Statistics Module as detailed as follows:
- Data transformations were performed, if appropriate, using the most suitable method. The homogeneity of variance from mean values was analyzed using Bartlett’s test. Intergroup variances were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covariates. Any transformed data were analyzed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for non-parametric data. If no dose response was found but the data showed non-homogeneity of means, the data were analyzed by a stepwise Dunnett’s (parametric) or Steel (non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric). - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no clinical signs at any dose level that were considered to be related to treatment with the test item.
Behavioral assessment scores across all treatment groups remained similar to the controls.
There were no treatment-related changes in functional performance at any dose level.
Sensory reactivity scores were comparable across all dose groups including controls. - Mortality:
- no mortality observed
- Description (incidence):
- There were no unscheduled deaths during the study.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was no detrimental effect of test item administration on body weight performance in animals of both sexes at any dose level.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on food intake or food conversion efficiency in animals of either sex receiving the test item at any dose level.
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on food intake or food conversion efficiency in animals of either sex receiving the test item at any dose level.
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- Visual inspection of water bottles did not indicate any intergroup differences in water intake.
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- Ophthalmoscopic examination of males and females from control and high dose groups during Week 12 of the study did not reveal any treatment-related differences.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Hematology evaluations did not reveal any toxicologically significant effects in animals of either sex resulting from treatment with the test item.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Blood chemistry evaluations did not indicate any treatment-related effects in animals of both sexes resulting from test item administration.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Behavioral assessment scores across all treatment groups remained similar to the controls.
There were no treatment-related changes in functional performance at any dose level.
Sensory reactivity scores were comparable across all dose groups including controls. - Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Minor macroscopic changes were noted which were considered not to be related to administration of the test item.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Normal variations in a number of background findings were noted but no consistent changes were noted which could be attributed to treatment after histopathology evaluation.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no intergroup differences considered to be of toxicological relevance.
- Details on results:
- There were no unscheduled deaths during the study. Throughout the dosing period, there were no clinical signs at any dose level that were considered to be related to treatment with the test item.
There were no changes in the behavioral parameters considered to be related to treatment with the test item at any dose level. There were no intergroup differences considered to be related to treatment with the test item at any dose level. Sensory reactivity scores across all treatment groups were comparable with controls.
There was no detrimental effect of treatment with the test item at any dose level on body weight development in animals of either sex. Throughout the treatment period, weekly food consumption and food conversion efficiency values for test item-treated males and females were generally similar to the respective controls. Visual inspection of water bottles did not reveal any overt intergroup differences. No treatment-related ocular changes were apparent in animals of both sexes from the high dose group in relation to the controls.
There were no hematological findings of toxicological significance at the end of the treatment period. There were no intergroup differences considered to be related to treatment with the test item.
Minor changes were noted at necropsy that were considered not to be related to administration of the test item. At 1000 mg/kg bw/day, group mean absolute and body weight-related kidneys and ovaries weights in females were marginally but statistically significantly lower than controls (p<0.05). All individual values from the high dose animals were within the historical control data ranges and in the absence of any relevant microscopic findings, these findings were considered to be of no toxicological importance. Normal variations in a number of background histopathological findings were noted but no consistent changes were noted which could be attributed to treatment after histopathology evaluation. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food efficiency
- Key result
- Critical effects observed:
- no
- Conclusions:
- Under the conditions of this study, the oral (gavage) administration of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine (CAS RN 15721-78-5) to male and female Wistar Han™:RccHan™:WIST strain rats at dose levels of up to 1000 mg/kg bw/day was well tolerated. There was no effect of treatment on body weight development and dietary intake in animals of either sex. Hematology, blood chemistry and microscopic examination of the selected tissues did not identify any findings of toxicological relevance and a dose level of 1000 mg/kg bw/day is considered to be the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity.
- Executive summary:
The study was designed to investigate the systemic toxicity of the test item, by repeated oral administration via gavage to the Wistar Han™: RccHan™: WIST strain rat for a period of ninety consecutive days at dose levels of 100, 300 or 1000 mg/kg bw/day. The study was conducted to OECD 408 Test Guidelines under GLP conditions. A control group of ten males and ten females was dosed concurrently with vehicle alone (Arachis oil BP). The oral route was selected as the most appropriate route of exposure, based on the physical propertiesof the test item, and the results of the study are believed to be of value in predicting the likely toxicity of the test item to man.
The dose levels were chosen in consultation with the Study Monitor for the Sponsor and were based on the preliminary data from a 14 day dose range-finding study in the rat (Envigo Study Number 41403760). In this range-finding study, administration of the test item to animals of either sex at dose levels of 250, 500 or 1000 mg/kg bw/day was well tolerated. There was no detrimental effect of treatment with the test item on body weight development or food consumption in males. Females receiving the test item at all dose levels showed sporadic instances of slightly reduced group mean body weight gains which resulted in slightly lower overall weight gains, albeit without any dose-relationship. Food consumption levels in these females were also generally slightly lower than those of the control animals, but there was no dose-dependence. There were no macroscopic findings for any of the animals and taking into consideration the overall results, a dose level of 1000 mg/kg bw/day was considered to be suitable for investigation in the current study together with 100 and 300 mg/kg bw/day as the low and intermediate dose levels, respectively.
Clinical signs, functional observations, body weight change, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Ophthalmoscopic examination was also performed on animals from all dose groups before the start of dosing and on control group and high dose animals during Week 12 of the treatment period.
All animals were subjected to gross necropsy examination, and histopathological evaluation of selected tissues from high dose and control animals was performed.
There were no unscheduled deaths during the study. Throughout the dosing period, there were no clinical signs at any dose level that were considered to be related to treatment with the test item.
There were no changes in the behavioral parameters considered to be related to treatment with the test item at any dose level. There were no intergroup differences considered to be related to treatment with the test item at any dose level. Sensory reactivity scores across all treatment groups were comparable with controls.
There was no detrimental effect of treatment with the test item at any dose level on body weight development in animals of either sex. Throughout the treatment period, weekly food consumption and food conversion efficiency values for test item-treated males and females were generally similar to the respective controls. Visual inspection of water bottles did not reveal any overt intergroup differences. No treatment-related ocular changes were apparent in animals of both sexes from the high dose group in relation to the controls.
There were no hematological findings of toxicological significance at the end of the treatment period. There were no intergroup differences considered to be related to treatment with the test item.
Minor changes were noted at necropsy that were considered not to be related to administration of the test item. At 1000 mg/kg bw/day, group mean absolute and body weight-related kidneys and ovaries weights in females were marginally but statistically significantly lower than controls (p<0.05). All individual values from the high dose animals were within the historical control data ranges and in the absence of any relevant microscopic findings, these findings were considered to be of no toxicological importance. Normal variations in a number of background histopathological findings were noted but no consistent changes were noted which could be attributed to treatment after histopathology evaluation.
Under the conditions of this study, the oral (gavage) administration of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine (CAS RN 15721-78-5) to male and female Wistar Han™:RccHan™:WIST strain rats at dose levels of up to 1000 mg/kg bw/day was well tolerated. There was no effect of treatment on body weight development and dietary intake in animals of either sex. Hematology, blood chemistry and microscopic examination of the selected tissues did not identify any findings of toxicological relevance and a dose level of 1000 mg/kg bw/day is considered to be the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity.
Reference
Deviation No.1
The Study Plan incorrectly indicated that assessment of pupillary and corneal blink reflex would be performed as part of the ophthalmic examination conducted during the study. These assessments are not part of the routine ophthalmic examinations required by the regulatory guidelines and were not performed, although assessment of pupil and blink reflex was performed as part of the Functional Observational Battery conducted during the study. This deviation from Study Plan was considered not to have had any impact on the scientific validity of the report.
Deviation No. 2
On 09 April 2015, (Days 49 and 48 of dosing for males and females, respectively), one hour post-dose clinical observations were performed with a delay of approximately one hour and 50 minutes. On 20 April 2015, (Days 60 and 59 of dosing for males and females, respectively), one hour post-dose clinical observations were performed with a delay of approximately 25 minutes. These delays occurred due to technician error. These incidents, occurred twice over the duration of the treatment period. Post-dose clinical observations on these days were performed and there were no treatment-related clinical signs for any of the animals throughout the dosing period. These deviations from the Study Plan were therefore considered not to have affected the scientific integrity of the study or the results obtained.
Deviation No.3
According to the Study Plan, animals were to be provided with Rodent 2014C Teklad Global Certified Pelleted Diet. Whilst recording dietary intake on 09 May 2015, food hoppers for the females were topped up with Rodent 2018C Teklad Global Certified Pelleted Diet, in error. This went unnoticed at the time and food hoppers for these females were topped up with the correct diet on 16 May 2015. The initial error resulted in all females on the study receiving a mixture of the two diets over Weeks 12 and 13 of dosing. From the amount of the diet residue left in the food hopper and the total amount given to the females on 09 May 2015, it is calculated that the diet mixture provided to the females on this day would have contained 25% to 41% of Rodent 2018C Teklad Global Certified Pelleted Diet and this percentage is considered likely to have gradually decreased over the two weeks. The main differences between the 2014C and 2018C pelleted diets is the slightly higher protein and fat content in the 2018C (approximately 4% and 2%, respectively) resulting in marginally higher energy density for this diet. As females from all dose groups, including controls, received a mixture of the two diets over the noted period and an evaluation of the relevant data did not identify any effects considered to be related to this mixing of the diets, this deviation from the Study Plan was considered not to have affected the scientific integrity of the study or the results obtained.
Deviation No.4
The Study Plan incorrectly stated that urinalysis parameters (urine volume and specific gravity) will be statistically analysed. No urinalysis was scheduled to be performed during this study and this deviation from the Study Plan had no impact on the scientific validity of the report.
See attachment for Tables.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- One key study is available to address the endpoint, with a Klimisch score of 1, performed to standardised guidelines under GLP conditions. Therefore, the quality of the database is considered to be good.
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
Oral route:
Repeated dose toxicity: oral. Key Study, Envigo Research Laboratories Ltd., 2017 Fourteen Day Repeated Dose Oral (gavage) Rangefinding Toxicity Study in the Rat
A 14-day rangefinding study was conducted to OECD 408 Test Guidelines under GLP conditions.
The study was designed to determine the effects of repeated oral administration ofbis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine (CAS RN 15721-78-5): to rats for fourteen consecutive days to provide toxicological data to assist in dose level selection for subsequent repeated dose oral toxicity studies.
The test item was administered by gavage to three groups, each of three male and three female Wistar Han™:RccHan™:WIST strain rats at dose levels of 250, 500 and 1000 mg/kg bw/day. A control group of three males and three females was dosed with vehicle alone (Arachis oil BP).
Clinical signs, body weight, dietary intake and water consumption were monitored during the study. All animals were subjected to gross necropsy examination at study termination.
There were no unscheduled deaths during the study. Throughout the treatment period, none of the animals on the study showed any clinical signs. When compared with controls, sporadic instances of slightly reduced group mean body weight gains were observed for females at all dose levels, which resulted in slightly lower overall weight gains for these animals, but without any dose-relationship.
Food consumption in females receiving the test item at all dose levels showed a marginal reduction in comparison with controls throughout the treatment period, albeit without any dose-relationship. Food conversion efficiency values in females were generally slightly lower than the respective controls, reflecting intergroup differences in body weight gains and/or food intake for these animals. No such effects were detected in males treated with 250, 500 or 1000 mg/kg bw/day. There was no evidence of any effect of treatment with the test item on water intake in animals of either sex. There were no macroscopic findings for animals of either sex at terminal necropsy.
Oral administration of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine (CAS RN 15721-78-5) to rats by gavage, for fourteen consecutive days, at dose levels of 250, 500 or 1000 mg/kg bw/day was associated with slightly lower overall group mean weight gains and marginally reduced food intake for females.
Administration of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine (CAS RN 15721-78-5) at all dose levels to Wistar Han:RccHan:WIST female rats for fourteen consecutive days was associated with slightly lower overall group mean weight gains and marginally reduced food intake. There was no dose-relationship and the overall magnitude of these effects was insufficient to exclude the high dose level from further investigations. As these effects were not observed in males at any dose level and there were no clinical signs or macroscopicfindings foranimals of either sex treated with the test item, a dose level of 1000 mg/kg bw/day is considered suitable for use as high dose in a subsequent oral (gavage) ninety day toxicity study in the rat.
Repeated dose toxicity: oral. Key Study, Envigo Research Laboratories Ltd., 2017 90-Day Repeated Dose Oral (gavage) Toxicity Study in the Rat
The study was designed to investigate the systemic toxicity of the test item, by repeated oral administration via gavage to the Wistar Han™: RccHan™: WIST strain rat for a period of ninety consecutive days at dose levels of 100, 300 or 1000 mg/kg bw/day. The study was conducted to OECD 408 Test Guidelines under GLP conditions. A control group of ten males and ten females was dosed concurrently with vehicle alone (Arachis oil BP). The oral route was selected as the most appropriate route of exposure, based on the physical propertiesof the test item, and the results of the study are believed to be of value in predicting the likely toxicity of the test item to man.
The dose levels were chosen in consultation with the Study Monitor for the Sponsor and were based on the preliminary data from a 14 day dose range-finding study in the rat (Envigo Study Number 41403760). In this range-finding study, administration of the test item to animals of either sex at dose levels of 250, 500 or 1000 mg/kg bw/day was well tolerated. There was no detrimental effect of treatment with the test item on body weight development or food consumption in males. Females receiving the test item at all dose levels showed sporadic instances of slightly reduced group mean body weight gains which resulted in slightly lower overall weight gains, albeit without any dose-relationship. Food consumption levels in these females were also generally slightly lower than those of the control animals, but there was no dose-dependence. There were no macroscopic findings for any of the animals and taking into consideration the overall results, a dose level of 1000 mg/kg bw/day was considered to be suitable for investigation in the current study together with 100 and 300 mg/kg bw/day as the low and intermediate dose levels, respectively.
Clinical signs, functional observations, body weight change, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Ophthalmoscopic examination was also performed on animals from all dose groups before the start of dosing and on control group and high dose animals during Week 12 of the treatment period.
All animals were subjected to gross necropsy examination, and histopathological evaluation of selected tissues from high dose and control animals was performed.
There were no unscheduled deaths during the study. Throughout the dosing period, there were no clinical signs at any dose level that were considered to be related to treatment with the test item.
There were no changes in the behavioral parameters considered to be related to treatment with the test item at any dose level. There were no intergroup differences considered to be related to treatment with the test item at any dose level. Sensory reactivity scores across all treatment groups were comparable with controls.
There was no detrimental effect of treatment with the test item at any dose level on body weight development in animals of either sex. Throughout the treatment period, weekly food consumption and food conversion efficiency values for test item-treated males and females were generally similar to the respective controls. Visual inspection of water bottles did not reveal any overt intergroup differences. No treatment-related ocular changes were apparent in animals of both sexes from the high dose group in relation to the controls.
There were no hematological findings of toxicological significance at the end of the treatment period. There were no intergroup differences considered to be related to treatment with the test item.
Minor changes were noted at necropsy that were considered not to be related to administration of the test item. At 1000 mg/kg bw/day, group mean absolute and body weight-related kidneys and ovaries weights in females were marginally but statistically significantly lower than controls (p<0.05). All individual values from the high dose animals were within the historical control data ranges and in the absence of any relevant microscopic findings, these findings were considered to be of no toxicological importance. Normal variations in a number of background histopathological findings were noted but no consistent changes were noted which could be attributed to treatment after histopathology evaluation.
Under the conditions of this study, the oral (gavage) administration of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine (CAS RN 15721-78-5) to male and female Wistar Han™:RccHan™:WIST strain rats at dose levels of up to 1000 mg/kg bw/day was well tolerated. There was no effect of treatment on body weight development and dietary intake in animals of either sex. Hematology, blood chemistry and microscopic examination of the selected tissues did not identify any findings of toxicological relevance and a dose level of 1000 mg/kg bw/day is considered to be the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity.
Inhalation route:
According to Column 2 of Annex VIII of the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation repeated dose toxicity: dermal route does not need to be conducted if exposure of humans is unlikely, taking into account the vapour pressure of the substance and the possibility of exposure to particles of inhalable size. Exposure of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine to humans via inhalation is considered minimal due to the very low vapour pressure (<0.000011Pa), the low potential of exposure from particles of inhalable size (particle size of 10% <52.296µm, 50% <400.623µm and 90% <1135.78µm) and appropriate Risk Management Measures (RMM) identified in the Chemical Safety Report.
Therefore, based upon low human exposure potential and available study data, this endpoint is waived.
Dermal route:
According to Column 2 of Annex VIII of the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation repeated dose toxicity: dermal route does not need to be conducted if exposure of humans is unlikely, taking into account any skin contact during production and the rate of absorption through the skin. Exposure of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine to humans via skin contact is considered minimal due to appropriate Risk Management Measures (RMM) identified in the Chemical Safety Report.
Therefore, based upon low human exposure potential and available study data, this endpoint is waived.
Justification for selection of repeated dose toxicity via oral
route - systemic effects endpoint:
An OECD Test Guideline 408: Repeated Dose 90-Day Oral Toxicity Study
in Rodents is proposed for the substance
Bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine (CAS number 15721-78-5; EC
number 239-816-9).
The Lead Registrant proposes an OECD 408 study to fulfill the data
requirements as specified under REACH for this tonnage level (Annex IX).
The lower tonnage bands allow for the completion of an OECD 407:
Repeated Dose 28-day Oral Toxicity Study in Rodents or an OECD 422:
Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test. Positive results in
an OECD 407 or OECD 422 , however, would likely result in the need to
conduct additional and/or more comprehensive studies. The OECD 408 study
is therefore proposed so as to meet the data requirements for REACH
Annex IX requirements and to meet the data requirements of the lower
tonnage bands. An OECD 408 is more comprehensive study and will assess
the repeated dose toxicity od the substance while also reducing animal
testing as fewer animals are required by conducting an OECD 408, rather
than conducting an OECD 407 and/or OECD 422.
Justification for selection of repeated dose toxicity inhalation -
systemic effects endpoint:
According to Column 2 of Annex VIII of the Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH) legislation repeated
dose toxicity: dermal route does not need to be conducted if exposure of
humans is unlikely, taking into account the vapour pressure of the
substance and the possibility of exposure to particles of inhalable
size. Exposure of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine to humans
via inhalation is considered minimal due to the very low vapour pressure
(<0.000011Pa), the low potential of exposure from particles of inhalable
size (particle size of 10% <52.296µm, 50% <400.623µm and 90% <1135.78µm)
and appropriate Risk Management Measures (RMM) identified in the
Chemical Safety Report.
Therefore, based upon low human exposure potential and available study
data, this endpoint is waived.
Justification for selection of repeated dose toxicity inhalation -
local effects endpoint:
According to Column 2 of Annex VIII of the Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH) legislation repeated
dose toxicity: dermal route does not need to be conducted if exposure of
humans is unlikely, taking into account the vapour pressure of the
substance and the possibility of exposure to particles of inhalable
size. Exposure of bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine to humans
via inhalation is considered minimal due to the very low vapour pressure
(<0.000011Pa), the low potential of exposure from particles of inhalable
size (particle size of 10% <52.296µm, 50% <400.623µm and 90% <1135.78µm)
and appropriate Risk Management Measures (RMM) identified in the
Chemical Safety Report.
Therefore, based upon low human exposure potential and available study
data, this endpoint is waived.
Justification for selection of repeated dose toxicity dermal -
systemic effects endpoint:
According to Column 2 of Annex VIII of the Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH) legislation repeated
dose toxicity: dermal route does not need to be conducted if exposure of
humans is unlikely, taking into account any skin contact during
production and the rate of absorption through the skin. Exposure of
bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine to humans via skin contact
is considered minimal due to appropriate Risk Management Measures (RMM)
identified in the Chemical Safety Report.
Therefore, based upon low human exposure potential and available study
data, this endpoint is waived.
Justification for selection of repeated dose toxicity dermal - local
effects endpoint:
According to Column 2 of Annex VIII of the Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH) legislation repeated
dose toxicity: dermal route does not need to be conducted if exposure of
humans is unlikely, taking into account any skin contact during
production and the rate of absorption through the skin. Exposure of
bis(4-(1,1,3,3-tetramethylbutyl)phenyl)amine to humans via skin contact
is considered minimal due to appropriate Risk Management Measures (RMM)
identified in the Chemical Safety Report.
Therefore, based upon low human exposure potential and available study
data, this endpoint is waived.
Justification for classification or non-classification
In accordance with The CLP Regulation. European Regulation (EC) No 1272/2008, the test item has been determined as not classified in relation to repeated dose toxicity.
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