Registration Dossier
Registration Dossier
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 404-360-3 | CAS number: 119313-12-1 CG 25-369; IRGACURE 369; TK 11-319
- 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
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 009
- Report date:
- 2009
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- (2008)
- Deviations:
- yes
- Remarks:
- No recovery was considered, only two doses used instead of three as recommended by guideline OECD 407.
- Principles of method if other than guideline:
- The study was based around the OECD guideline 407, which however, was not fully applicable as this study was intended for dose selection for a follow up 90-day study in rats. No recovery was considered; only two doses were used instead of three as recommended by guideline. The dose level of 250 mg/kg bw/day was established as LOAEL. Animals of this group were initially treated with 500 mg/kg bw/day. However, since severe toxicity was seen, treatment was stopped after 9 days, followed by a 5 day recovery period. Subsequently, dosing of these animals was decreased to 250 mg/kg bw/d. Therefore, it could not be excluded that the initial dosing with 500 mg/kg bw/day had, to some degree, contributed to the overall toxicity on which the LOAEL was based.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2-benzyl-2-dimethylamino-4'-morpholinobutyrophenone
- EC Number:
- 404-360-3
- EC Name:
- 2-benzyl-2-dimethylamino-4'-morpholinobutyrophenone
- Cas Number:
- 119313-12-1
- Molecular formula:
- C23 H30 N2 O2
- IUPAC Name:
- 2-benzyl-2-(dimethylamino)-1-[4-(morpholin-4-yl)phenyl]butan-1-one
- Details on test material:
- - Physical state: solid (yellow powder)
- Analytical purity: 99.9 %
- Lot/batch No.: 37973FC4AA
- Expiration date of the lot/batch: 2010-12-01
- Stability under test conditions: stable, solutions of test article are sensitive to light
- Storage condition of test material: At room temperature protected from sunlight
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 10 weeks (males), 9 weeks (females)
- Weight at study initiation: 288 - 293 (males), 174 - 180 (females)
- Housing: in groups of 5 per sex in Macrolon cages (MIV type)
- Diet ad libitum: pelleted rodent diet (SM R/M-Z from SSNIFF Spezialdiäten GmbH)
- Water ad libitum: tap water
- Acclimatisation: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.7 - 21.7
- Humidity (%): 37 - 72 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on oral exposure:
- The choice of vehicle was based on trial formulations performed at NOTOX and on information from the sponsor.
Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenised to a visually acceptable level. Formulations were kept away from light as much as possible using amber coloured glassware and/or tin foil. Correction was made for specific gravity of the vehicle. - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Analysis of stability, homogeneity and concentration of the test article under test conditions was not performed as part of the present study. According to the author, such analyses were to be done within a one-generation reproduction toxicity study performed later.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Remarks:
- Reduced to 250 mg/kg bw/day after 9 treatment days a 5 recovery days.
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- The test substance, formulated in vehicle, was administered daily for 28 days by oral gavage to the rats. After 9 days and because of severe toxicity, treatment with the highest dose level of 500 mg/kg bw/day (group 3) was stopped for a period of five days (recovery); Subsequently, the same animals were dosed with 250 mg/kg bw/day for 28 days.
Examinations
- Observations and examinations performed and frequency:
- MORTALITY AND CLINICAL OBSERVATIONS
The animals were checked for mortality at least twice daily and were examined at least daily for clinical signs.
BODY WEIGHT
Weekly, and additionally on day 11; terminal body weight was also assessed.
FOOD CONSUMPTION
Weekly
HAEMATOLOGY AND CLINICAL CHEMISTRY
Blood samples were collected under iso-flurane anaesthesia on the day of sacrifice after a over night fasting. For details on parameters see table 1. - Sacrifice and pathology:
- GROSS PATHOLOGY
All animals were anaesthetized at test ending using iso-flurane and subsequently exsanguinated. After gross pathology the following tissues and organs were collected from all animals and fixed: Lung, adrenal glands, spleen, epididymides, sternum with bone marrow, kidneys, testes, liver and all gross lesions.
From all males sperm samples were taken from the proximal part of the vas deferens to assess sperm motility.
Organ weights: Adrenal glands, liver, kidneys, spleen
HISTOPATHOLOGY
Organ and tissue samples were processed, embedded, cut and stained for histopathology.
All tissues and organs collected at the scheduled sacrifice from all animals of the control and the highest dose group, the samples of the testes of groups 1 and 3 (examination of spermatogenesis) and all gross lesions were examined.
Based on treatment-related morphologic changes in the liver, kidneys, adrenal glands, and sternum with bone marrow of group 3 males and/or females, these organs were also examined from all animals of Group 2 (males and females; kidneys were examined for males only). - Statistics:
- The following statistical methods were used to analyse the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- The exact Fisher-test was applied to frequency data.
- The percentage of motile spermatozoa and progressive motile spermatozoa were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup difference.
If the results of the ANOVA were significant (p < 0.05), the Wilcoxon test was applied to the data to compare the treated groups to the control group.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Clinical signs consisted of hunched posture, piloerection, a lean appearance, salivation, retching and/or gasping among animals at 500 mg/kg bw/day. These symptoms resolved during the wash-out period of 5 days. During the subsequent treatment at 250 mg/kg bw/day, no toxicologically relevant clinical signs were observed.
One case of rales was seen for 1 female at 250 mg/kg bw/day. This is commonly noted in rats of this age and strain under the conditions in this study.
Salivation was noted intermittently among most animals at 250 mg/kg bw/day as well as among most females at 100 mg/kg bw/day. This effect was considered to be of non-toxicological relevance. No clinical signs were noted among control animals and males at 100 mg/kg bw/day. - Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study period.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight loss (up to 14% of the weight recorded on Day 1) or reduced weight gain was noted among all animals at 500 mg/kg bw/day (see figure). At commencement of treatment at 250 mg/kg/day, body weights of females were similar to control values, whilst body weights of males were still slightly lower than control levels (achieving level of statistical significance). During the first two weeks of treatment at 250 mg/kg bw/day, body weight gain of this group was similar to control levels (taking Day 15 as reference point). Although body weight gain in the last two weeks of treatment could not be compared to concurrent control levels (control animals were sacrificed after 28 days), body weight gain was in the range to be expected for rats of this age and strain.
A statistically significant higher body weight gain of females at 100 mg/kg bw/day on day 15 remained within the range considered normal for rats of this age and strain. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A lower (relative) food consumption was noted for males and females at 500 mg/kg bw/day, which recovered to control levels after the recovery period.
For females at 250 mg/kg bw/day, relative food consumption appeared slightly higher than control levels. This was due to slightly higher food consumption, as was also observed for females at 100 mg/kg bw/day. Since food consumption levels for these animals remained within the range considered normal, this was considered to be of no toxicological relevance. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The following changes in hematology parameters were of statistical significance in comparison to control animals:
Higher prothrombin time (PT) in males at 100 and 250 mg/kg bw/day, lower reticulocyte and platelet counts in males at 250 mg/kg bw/day, lower hemoglobin concentration and activated partial thromboplastin time (APTT) in females at 250 mg/kg bw/day. However, the both latter effects were within the range considered normal for rats of this age and strain.
Other hematological parameters of animals at 100 and 250 mg/kg bw/day were similar to control values. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The following in clinical biochemistry parameters were of statistical significance in comparison to control animals:
Higher alanine aminotransferase activity in males at 250 mg/kg bw/day, and in females at 100 and 250 mg/kg bw/day (not statistically significant at 250 mg/kg bw/day), higher inorganic phosphate levels in females at 250 mg/kg bw/d, lower total protein levels in males at 250 mg/kg bw/day, lower urea levels in males at 250 mg/kg/day, lower sodium levels in males at 250 mg/kg bw/day, lower chloride levels in males and females at 250 mg/kg bw/day. However, the four latter effects were within the range considered normal for rats of this age and strain.
Other clinical biochemistry parameters of animals at 100 and 250 mg/kg/day were similar to control values. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- The liver weight and liver to body weight ratio was higher in males and females at 100 and 250 mg/kg bw/day. A lower spleen weight was recorded for females at 250 mg/kg bw/day, while spleen to body weight ratio was lower for females at 100 and 250 mg/kg bw/day. Kidney and adrenal weights of animals at 100 and 250 mg/kg bw/day were similar to control levels.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At macroscopic examination greenish discolouration of the kidneys was observed among all animals at 250 mg/kg bw/day. Redbrown discolouration of the liver was noted among most females at 250 mg/kg bw/day.
Other necropsy findings included dark-red foci on the pancreas, enlarged adrenal glands, tan discolouration of adrenal glands, and pelvic dilation of the kidneys. These changes were not accompanied by treatment-related histopathological correlates, and hence these were considered not to be of toxicological relevance.
No abnormalities were noted at necropsy of control animals and females at 100 mg/kg bw/day. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- The following histopathological changes were considered to be related to treatment with the test substance:
Liver: Hypertrophy of the hepatocytes in 4/5 males and 5/5 females of group 3.
Kidneys (males): increased incidence and severity of cortical hyaline droplets in Groups 2 (5/5 males) and 3 (4/5 males). In Group 1 this was seen in 2/5 males at a minimal degree. In this study the occurrence of cortical hyaline droplets was accompanied by a slightly increased incidence and severity of corticomedullary tubular basophilia in Groups 2 (3/5 animals) and 3 (4/5 animals). No tubular basophilia was recorded in males of Group 1 (control).
Bone marrow-sternal: Myeloid atrophy in the sternal bone-marrow in Group 3 in 3/5 males and 3/5 females.
The staging of spermatogenesis of the animals of Groups 1 and 3 suggested normal spermatogenesis; all stages were present.
All other microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both, control and treated rats. - Other effects:
- no effects observed
- Description (incidence and severity):
- Upon investigation of sperm motility no abnormalities up to 250 mg/kg bw/day were seen.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- gross pathology
- haematology
- organ weights and organ / body weight ratios
- Dose descriptor:
- LOAEL
- Effect level:
- 250 - 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Selected clinical chemistry parameters for females
control | 100 mg/kg bw | 250 (500) mg/kg bw | |
ALAT (U/L) | 41.4 | 63.5 * | 59.9 |
ASAT (U/L) | 69 | 75.9 | 67.6 |
ALP (U/L) | 67 | 93 | 78 |
Urea (mmol/L) | 9.8 | 8.5 | 9.5 |
Table 2: Selected clinical chemistry parameter for males
control | 100 mg/kg bw | 250 (500) mg/kg bw | |
ALAT (U/L) | 43.2 | 47.7 | 53.4 |
ASAT (U/L) | 77 | 71.3 | 83.4 |
ALP (U/L) | 173 | 154 | 150 |
Urea (mmol/L) | 10.6 | 8.6 | 7.2* |
Table 3a and b: Absolute body and liver weights for males and females
males | control | 100 mg/kg bw | 250 (500) mg/kg bw |
body weights (g) | 338 | 331 | 320 |
liver weights (g) | 8.63 | 9.78 ** | 10.76 ** |
females | control | 100 mg/kg bw | 250 (500) mg/kg bw |
body weights (g) | 190 | 197 | 197 |
liver weights (g) | 5.23 | 6.28 * | 7.63 ** |
Table 4a and b: Selected haematology parameters for males and females
males | control | 100 mg/kg bw | 250 (500) mg/kg bw |
Haemoglobin, mmol/L | 9.8 | 9.6 | 9.4 |
APTT, s | 16.9 | 18.2 | 16.2 |
Females | control | 100 mg/kg bw | 250 (500) mg/kg bw |
Haemoglobin, mmol/L | 9.5 | 9.2 | 9.0* |
APTT, s | 16.9 | 18.7 | 13.9* |
Table 5: Sperm Motility Summary
control | 100 mg/kg bw | 500 mg/kg bw | |
Motility | |||
Mean | 55 | 61 | 45 |
St. Dev. | 22 | 23 | 26 |
N | 5 | 5 | 5 |
Progressive Motility | |||
Mean | 32 | 29 | 24 |
St. Dev. | 12 | 10 | 16 |
N | 5 | 5 | 5 |
Applicant's summary and conclusion
- Conclusions:
- Clear toxicological effects were observed in the 500 mg/kg bw/day dose group at 9 days, this group was subsequently placed on a 5 day recovery period and resumed dosing at 250 mg/kg bw/day for the remainer of the test duration. None adverse effects (haematology, clinical biochemistry, gross necropsy, and organ weight) were observed in the 100 mg/kg bw/day group. The 28 day repeat dose NOAEL for systemic toxicity was therefore set at 100 mg/kg bw/day.
- Executive summary:
In this study conducted to generally accepted scientific standards with GLP, the test material (EC 404-360-3) was administered daily via gavage (using propylene glycol as a vehicle) to rats of both sexes in doses of 0, 100 amd 500 mg/kg bw/day. Due to severe toxicity after 9 days, the 500 mg/kg bw/day was stopped for 5 days, before the same animals were re-dosed with a lower amount of 250 mg/kg bw/day for 28 days. Toxic effects were still observed at this level but not at the 100 mg/kg bw/day dose. Thus, the test material was determined to have a NOAEL of 100 mg/kg bw/day and a LOAEL of 250-500 mg/kg bw/day, however, it is not possible to completely exclude that the toxic effects observed at the 250 mg/kg bw/day was due to the previous dosing of 500 mg/kg bw/day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
