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EC number: 941-634-6 | CAS number: 1228284-78-3
- 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
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 18 September 2016 to 26 June 2017
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
- Remarks:
- New studies were conducted solely to comply with a non-EU national registration requirement, and have been included in the dossier in accordance with REACH, Article 22(1)e. The study was conducted under a National quality assurance scheme (HJ/T 155-2004) similar to OECD GLP.
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
- toxicokinetics
- Qualifier:
- according to guideline
- Guideline:
- other: The guidelines for the testing of chemicals (health effects, version 2) issued by the Ministry of Environmental Protection of the People's Republic of China in September 2013 (417, Toxicokinetics).
- Deviations:
- no
- GLP compliance:
- no
- Remarks:
- The study was conducted under a National quality assurance scheme (HJ/T 155-2004) similar to OECD GLP.
- Radiolabelling:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Beijing WeiTongLiHua Test Animal Technology Co. Ltd.
- Age at study initiation: 6-8 weeks for males and females
- Weight at study initiation: 184.7 – 263.4 g (6 female rats) and 249.5 - 292 g (34 male rats)
- Housing: Transparent polycarbonate cages. Bedding was changed twice a week.
- Diet (e.g. ad libitum): Standard feed for test animal, ad libitum, Beijing Keao Xieli Feed Co. Ltd, SCXK (JING) 2014-0010.
- Water (e.g. ad libitum): RO water, ad libitum.
- Acclimation period: The animals were acclimatised and observed for at least 7 days prior to dosing. During this period, no abnormalities of the animals were observed.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25°C
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): Alternating 12-hour light and dark cycles - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Duration and frequency of treatment / exposure:
- Different test goups were either given a single dose or repeat dosed for 7 days
- Dose / conc.:
- 50 mg/kg bw (total dose)
- Remarks:
- single dose for toxicokinetics, tissue distribution and excretion groups
- Dose / conc.:
- 500 mg/kg bw (total dose)
- Remarks:
- signle dose toxicokinetics
- Dose / conc.:
- 50 mg/kg bw/day
- Remarks:
- 7 day, repeat dose for toxicokinetics
- No. of animals per sex per dose / concentration:
- 4 males in the TK studies, 2 males and 2 females in the tissue distribution study
- Control animals:
- no
- Details on dosing and sampling:
- DOSING: Single or repeat doses of test material were administered to each rat by oral gavage in a dose volume of 10 mL/kg. Feed was withheld from the animals for 12 hours prior to dosing.
SAMPLING:
TOXICOKINETIC STUDIES
- Tissues and body fluids sampled (delete / add / specify): Whole blood (ca 0.2 mL) was removed from each rat from the orbital venous plexus, the whole blood was collected into heparinised tubes and stored on ice. Plasma was separated from the red blood cells by centrifugation.
- Time and frequency of sampling:
50 mg/kg, single oral gavage: 5, 15 and 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours
500 mg/kg, single oral gavage: 5, 15 and 30 minutes, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours
50 mg/kg, repeat oral gavage: 5, 15 and 30 minutes and 1, 2, 4, 6, 8, 12 and 24 hours post administration days 1 and 7 and pre-dose, days 3-7
TISSUE DISTRIBUTION STUDY
- Tissues and/or body fluid, such as blood, heart, liver, spleen, lung, kidney and gastrointestinal tract and its contents, testes or ovaries, uterus or epididymis, muscle, eye, brain, thyroid gland, and fat
- Time and frequency of sampling:
0.5, 4 and 24 hours post administration
EXCRETION STUDY
- Urine and faeces samples were collected individually and separately from the rats in the excretion experiment at the following time points: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96 and 96-120 hours post administration.
- Bile was collected individually from the cannulated rats in the biliary excretion experiment at the following time points: 0-1, 1-2, 2-4, 4-8, 8-12, 12-24, 24-36, 36-48 hours post administration. - Statistics:
- For all batches, the calibration standard and quality control sample data were considered satisfactory with reference to the assay acceptance criteria and pharmacokinetic analysis was based upon the reported data. Acceptance criteria for standard curve: at least six point accuracy between 85% and 115%, calculation with standard curve regression, the correlation coefficient for standard curve is >0.99. Acceptance criteria for QC sample: at least 2/3 QC sample (at three concentrations) accuracy between 85% and 115%.
- Preliminary studies:
- In preliminary studies where the substance was administered as a single oral dose (20 and 1000 mg/kg), although the concentration-time profiles were variable amongst the animals following single oral administration (20 or 1000 mg/kg) of the substance, the mean AUC0-t for the male and female rats were similar and therefore, with the exception of the tissue distribution study, only male rats were used in the main tests. Since the concentration-times profiles for the male and female 1000 mg/kg oral dose groups were not well characterised, to the extent that the terminal phases for the individual animals were not made apparent, a 500 mg/kg oral dose group was used in the main study for the top dose. The low oral dose groups for the main studies were set at 50 mg/kg, 10-fold less than the 500 mg/kg dose.
- Details on absorption:
- Following single oral administrations of CA5204A to male rats (n = 4), a supraportional increase in CA5204A systemic exposure (AUC0-∞) was observed between 50 and 500 mg/kg, however, the CA5204A oral bioavailability for the 50 mg/kg (26.1±6.14%) and 500 mg/kg (150.6±18.3%) doses have been determined using the AUC0-t and should therefore be considered an underestimate of the absolute oral bioavailability.
Following 7 days repeat oral administration of 50 mg/kg/day CA5204A to male rats (n = 4/group) CA5204A predose concentrations in the plasma were approximately 2-fold greater than the LLOQ (50 ng/mL) and an increase (approximately 2-fold) in the mean CA5204A systemic exposure (AUC0-t) of the last exposure group was observed, compared to the mean CA5204A systemic exposure of the first group. - Details on distribution in tissues:
- Following single oral administration of 50 mg/kg CA5204A to male and female rats, CA5204A was widely and rapidly distributed across all tissues. Concentrations of CA5204A were higher for all tissues, compared to plasma and the tissues having the highest concentrations were the excretion organs (kidney and liver) and the fat. Peak tissue concentrations were reached by 4 hours and for the male rats the concentrations then declined in line with plasma for most of the tissues. For the male fat and epididymis and the female fat, muscle, ovary, uterus and eye, unlike plasma, concentrations of CA5204A were maintained until 24 hours.
- Details on excretion:
- Following single oral administration of 50 mg/kg CA5204A to male rats, the pattern of excretion was similar between the animals. Although low, the major route of excretion of CA5204A was predominantly via the faeces, with 2.30-5.26% of the dose being recovered by 120 hours. Elimination via the urine was a minor route of excretion, with ≤0.01% being recovered by 120 hours.
- Test no.:
- #2
- Toxicokinetic parameters:
- AUC: 9212 ng/ml*h
- Remarks:
- mean
- Test no.:
- #2
- Toxicokinetic parameters:
- half-life 1st: 5.17 h
- Remarks:
- mean
- Test no.:
- #2
- Toxicokinetic parameters:
- Tmax: 6 h
- Remarks:
- mean
- Test no.:
- #2
- Toxicokinetic parameters:
- Cmax: 1454 ng/mL
- Remarks:
- mean
- Test no.:
- #3
- Toxicokinetic parameters:
- AUC: 547502 ng/L*h
- Remarks:
- mean
- Test no.:
- #3
- Toxicokinetic parameters:
- half-life 1st: 10.1 h
- Remarks:
- mean
- Test no.:
- #3
- Toxicokinetic parameters:
- Tmax: 12 h
- Remarks:
- mean
- Test no.:
- #3
- Toxicokinetic parameters:
- Cmax: 23259 ng/L
- Remarks:
- mean
- Test no.:
- #4
- Toxicokinetic parameters:
- AUC: 9212 ng/mL*h
- Remarks:
- mean first group
- Test no.:
- #4
- Toxicokinetic parameters:
- half-life 1st: 5.62 h
- Remarks:
- mean first group
- Test no.:
- #4
- Toxicokinetic parameters:
- Tmax: 6 h
- Remarks:
- meran first group
- Test no.:
- #4
- Toxicokinetic parameters:
- Cmax: 1454 ng/mL
- Remarks:
- mean first group
- Test no.:
- #4
- Toxicokinetic parameters:
- AUC: 18840 ng/mL*h
- Remarks:
- mean 2nd group
- Test no.:
- #4
- Toxicokinetic parameters:
- half-life 1st: 4.21 h
- Remarks:
- mean 2nd group
- Test no.:
- #4
- Toxicokinetic parameters:
- Tmax: 4 h
- Remarks:
- mean 2nd group
- Test no.:
- #4
- Toxicokinetic parameters:
- Cmax: 2455 ng/mL
- Remarks:
- mean 2nd group
- Metabolites identified:
- not measured
- Conclusions:
- Following oral (50 and 500 mg/kg) administration of CA5204 to male rats, the data indicate that CA5204A is a low clearance (CLz = 1.25±0.130 L/h/kg) compound that non-specifically distributes into tissues and is eliminated with a half-life of ca. 3.25 – 7.49 hours for the 50 mg/kg dose group and 10.1±2.30 hours for the 500 mg/kg dose group. A supraportional increase in systemic exposure (AUC0-∞) of CA5204A in male rat plasma was observed between 50 and 500 mg/kg. The oral bioavailability of CA5204A in male rat plasma for the 50 mg/kg (19.1-23.6%) and 500 mg/kg (132-159%) dose groups has been determined using the AUC0-t and should therefore be considered an underestimate of the absolute oral bioavailability. Following repeat oral administration to male rats, CA5204A predose concentrations in the plasma were approximately 2-fold greater than the LLOQ (50 ng/mL) and an increase (approximately 2-fold) in the mean CA5204A systemic exposure (AUC0-t) of the last exposure group was observed, compared to the mean CA5204A systemic exposure of the first group. CA5204A was found to be a substrate for P450 mediated metabolism across species when incubated with liver microsomes or recombinant human P450 enzymes and was also found to have a high affinity for binding to rat dog and human plasma proteins.
- Executive summary:
The purpose of the in vivo studies was to reveal the toxicokinetic characteristics of the test substance in the rat, to inform on the absorption, distribution, metabolism and excretion processes and characteristics. The study was also not conducted to Good Laboratory Practice Standards as defined by the OECD but according to Ministry of Environmental Protection of the Peoples Republic of CHINA: HJ/T 155-2004; the guidelines for chemical testing good laboratory practices, implemented in June 2004.
Following single oral administrations of CA5204A to male rats (n = 4), a supraportional increase in CA5204A systemic exposure (AUC0-∞) was observed between 50 and 500 mg/kg, however, the CA5204A oral bioavailability for the 50 mg/kg (26.1±6.14%) and 500 mg/kg (150.6±18.3%) doses have been determined using the AUC0-t and should therefore be considered an underestimate of the absolute oral bioavailability.
Following 7 days repeat oral administration of 50 mg/kg/day CA5204A to male rats (n = 4/group) CA5204A predose concentrations in the plasma were approximately 2-fold greater than the LLOQ (50 ng/mL) and an increase (approximately 2-fold) in the mean CA5204A systemic exposure (AUC0-t) of the last exposure group was observed, compared to the mean CA5204A systemic exposure of the first group. Following single oral administration of 50 mg/kg CA5204A to male and female rats, CA5204A was widely and rapidly distributed across all tissues which is reflective of the high volume of distribution that was determined following single IV administration of 5 mg/kg to male and female rats. Concentrations of CA5204A were higher for all tissues, compared to plasma and the tissues having the highest concentrations were the excretion organs (kidney and liver) and the fat. Peak tissue concentrations were reached by 4 hours and for the male rats, concentrations then declined in line with plasma for the majority of the tissues. For the male fat and epididymis and the female fat, muscle, ovary, uterus and eye, unlike plasma, concentrations of CA5204A were maintained until 24 hours.
Following single oral administration of 50 mg/kg CA5204A to male rats (n = 4), the pattern of excretion was similar between the animals. Although low, the major route of excretion of CA5204A was predominantly via the faeces, with 2.30-5.26% of the dose being recovered by 120 hours. Elimination via the urine was a minor route of excretion, with ≤0.01% being recovered by 120 hours. Following IV bolus administration of 5 mg/kg CA5204A to male rats, excretion via the bile was very low, with ca. 0.03% of the administered dose being recovered by 48 hours.
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 18 September 2016 to 26 June 2017
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
- Remarks:
- New studies were conducted solely to comply with a non-EU national registration requirement, and have been included in the dossier in accordance with REACH, Article 22(1)e. The study was conducted under a National quality assurance scheme (HJ/T 155-2004) similar to OECD GLP.
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
- toxicokinetics
- Qualifier:
- according to guideline
- Guideline:
- other: The guidelines for the testing of chemicals (health effects, version 2) issued by the Ministry of Environmental Protection of the People's Republic of China in September 2013 (417, Toxicokinetics).
- Deviations:
- no
- GLP compliance:
- no
- Remarks:
- The study was conducted under a National quality assurance scheme (HJ/T 155-2004) similar to OECD GLP.
- Radiolabelling:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Beijing WeiTongLiHua Test Animal Technology Co. Ltd.
- Age at study initiation: 6-8 weeks for males and females
- Weight at study initiation: 184.7 – 263.4 g (6 female rats) and 249.5 - 292 g (34 male rats)
- Housing: Transparent polycarbonate cages. Bedding was changed twice a week.
- Diet (e.g. ad libitum): Standard feed for test animal, ad libitum, Beijing Keao Xieli Feed Co. Ltd, SCXK (JING) 2014-0010.
- Water (e.g. ad libitum): RO water, ad libitum.
- Acclimation period: The animals were acclimatised and observed for at least 7 days prior to dosing. During this period, no abnormalities of the animals were observed.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25°C
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): Alternating 12-hour light and dark cycles - Route of administration:
- intravenous
- Vehicle:
- other: DMSO: polyoxyethylene castor oil: saline solution (0.1: 0.65: 4.25, v/v/v) and further diluted with 35 mL of a physiological saline solution
- Duration and frequency of treatment / exposure:
- single dose
- Dose / conc.:
- 5 mg/kg bw (total dose)
- No. of animals per sex per dose / concentration:
- 4 males
- Control animals:
- no
- Details on dosing and sampling:
- DOSING: Single doses of test material were administered to each rat by IV bolus in a dose volume of 10 mL/kg. Feed was withheld from the animals for 12 hours prior to dosing.
SAMPLING:
- Tissues and body fluids sampled (delete / add / specify): Whole blood (ca 0.2 mL) was removed from each rat from the orbital venous plexus, the whole blood was collected into heparinised tubes and stored on ice. Plasma was separated from the red blood cells by centrifugation.
- Time and frequency of sampling: 1, 5, 15 and 30 minutes and 1, 2, 4, 6, 8, 12 and 24 hours - Statistics:
- For all batches, the calibration standard and quality control sample data were considered satisfactory with reference to the assay acceptance criteria and pharmacokinetic analysis was based upon the reported data. Acceptance criteria for standard curve: at least six point accuracy between 85% and 115%, calculation with standard curve regression, the correlation coefficient for standard curve is >0.99. Acceptance criteria for QC sample: at least 2/3 QC sample (at three concentrations) accuracy between 85% and 115%.
- Preliminary studies:
- Following IV bolus administration of 5 mg/kg of the test substance to male and female rats, concentration vs time profiles were consistent between the animals, with systemic exposure (AUC0-∞) to the test substance being equivalent for male and female rats. The preliminary data suggests that the test substance is moderately cleared compound that widely distributes into tissues, as indicated by the volume of distribution, approximately 10-fold the total body water of the rat.
- Details on absorption:
- Following IV bolus administration of 5 mg/kg of the test substance to male rats, concentration-time profiles were consistent between the animals. The data indicates that the substance is a low clearance compound that widely distributes into tissues, as indicated by the volume of distribution, approximately 15-fold the total body water of the rat. Although the same study design and dose formulation was employed for the main and preliminary IV studies, the lower clearance and higher volume of distribution for the animals in the main study resulted in longer (ca. 2-3-fold) test substance half-lives and increased (ca. 2-fold) systemic exposure compared to the preliminary animals. These differences in TK parameters can be attributed to natural variation between the animals.
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 3532 ng/ml*h
- Remarks:
- mean
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: 5.74 h
- Remarks:
- mean
- Test no.:
- #1
- Toxicokinetic parameters:
- other: MRT: 4.63 h
- Remarks:
- mean
- Test no.:
- #1
- Toxicokinetic parameters:
- other: CL: 1.25 L/h/kg
- Remarks:
- mean
- Test no.:
- #1
- Toxicokinetic parameters:
- other: V 10.32 L/kg
- Remarks:
- mean
- Metabolites identified:
- not measured
- Conclusions:
- Following IV bolus administration of 5 mg/kg test substance to male rats, concentration-time profiles were consistent between the animals. The data indicates that the substance is a low clearance compound that widely distributes into tissues, as indicated by the volume of distribution, approximately 15-fold the total body water of the rat. Although the same study design and dose formulation was employed for the main and preliminary IV studies, the lower clearance and higher volume of distribution for the animals in the main study resulted in longer (ca. 2-3-fold) substance half-lives and increased (ca. 2-fold) systemic exposure compared to the preliminary animals. These differences in TK parameters can be attributed to natural variation between the animals.
- Executive summary:
The purpose of the in vivo studies was to reveal the toxicokinetic characteristics of the test substance in the rat, to inform on the absorption, distribution, metabolism and excretion processes and characteristics. The study was also not conducted to Good Laboratory Practice Standards as defined by the OECD but according to Ministry of Environmental Protection of the Peoples Republic of CHINA: HJ/T 155-2004; the guidelines for chemical testing good laboratory practices, implemented in June 2004.
The data obtained following IV bolus administration of 5 mg/kg CA5204A to male rats (n = 4) indicate CA5204A is a low clearance compound (CLz = 1.25±0.130 L/h/kg) that widely distributes into tissues, as indicated by the volume of distribution (Vz = 10.32±1.86), approximately 15-fold the total body water of the rat.
Referenceopen allclose all
Table 2. Concentration of test substance (ng/mL) in male rat plasma following 50 mg/kg oral gavage administration
Time (h) |
R01 |
R02 |
R03 |
R04 |
Mean |
SD |
0.083 |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
|
0.25 |
68.7 |
63.4 |
100 |
62.0 |
73.6 |
18.0 |
0.5 |
104 |
160 |
207 |
137 |
152 |
43.2 |
1 |
137 |
253 |
568 |
197 |
289 |
192 |
2 |
397 |
668 |
693 |
439 |
549 |
153 |
4 |
291 |
1409 |
637 |
1132 |
867 |
499 |
6 |
493 |
1924 |
1327 |
697 |
1110 |
649 |
8 |
1047 |
806 |
1001 |
602 |
864 |
204 |
12 |
1435 |
715 |
747 |
202 |
775 |
506 |
24 |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ - Below the Lower Limit of Quantification, LOQ = 50 ng/mL
Table 3. Concentration of test substance (ng/mL) in male rat plasma following 500 mg/kg oral gavage administration
Time (h) |
R01 |
R02 |
R03 |
R04 |
Mean |
SD |
0.083 |
56.0 |
259 |
77.2 |
169 |
140 |
93.1 |
0.25 |
797 |
1971 |
1301 |
1215 |
1321 |
486 |
0.5 |
1438 |
2566 |
2304 |
1834 |
2035 |
501 |
1 |
2802 |
3171 |
5584 |
3515 |
3768 |
1245 |
2 |
3967 |
5503 |
7028 |
5338 |
5459 |
1252 |
4 |
7158 |
5481 |
12078 |
5680 |
7757 |
3385 |
6 |
5989 |
3278 |
15009 |
4906 |
7296 |
5262 |
8 |
5392 |
2921 |
23086 |
11154 |
10638 |
8987 |
12 |
4348 |
25943 |
24744 |
29978 |
21003 |
11246 |
24 |
13371 |
10041 |
9389 |
9314 |
10529 |
1923 |
36 |
10406 |
5380 |
5944 |
5837 |
6892 |
2356 |
48 |
8449 |
3092 |
3653 |
3613 |
4702 |
2511 |
72 |
420 |
463 |
762 |
677 |
581 |
165 |
96 |
BLLOQ |
BLLOQ |
72.5 |
66.1 |
BLLOQ |
BLLOQ - Below the Lower Limit of Quantification, LOQ = 50 ng/mL
Table 4. Concentration of test substance (ng/mL) in male rat plasma following 50 mg/kg oral gavage administration - first exposure group
Time (h) |
R01 |
R02 |
R03 |
R04 |
Mean |
SD |
0.083 |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
|
0.25 |
68.7 |
63.4 |
100.3 |
62.0 |
73.6 |
18.0 |
0.5 |
104 |
160 |
207 |
137 |
152 |
43 |
1 |
137 |
253 |
568 |
197 |
289 |
192 |
2 |
397 |
668 |
693 |
439 |
549 |
153 |
4 |
291 |
1409 |
637 |
1132 |
867 |
499 |
6 |
493 |
1924 |
1327 |
697 |
1110 |
649 |
8 |
1047 |
806 |
1001 |
602 |
864 |
204 |
12 |
1435 |
715 |
747 |
202 |
775 |
506 |
24 |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ - Below the Lower Limit of Quantification, LOQ = 50 ng/mL
Table 5. Pre-dose concentration of test substance (ng/mL) in male rat plasma following oral gavage administration of 50 mg/kg/day for 7 days
Time (h) |
L01 |
L02 |
L03 |
L04 |
Mean |
SD |
24 |
BLLOQ |
BLLOQ |
99.7 |
50.6 |
75.2 |
34.7 |
48 |
55.0 |
52.9 |
124 |
79.3 |
77.9 |
33.2 |
72 |
89.7 |
81.2 |
231 |
89.9 |
123 |
72.1 |
96 |
102 |
86.4 |
147 |
119 |
114 |
26.0 |
120 |
93.1 |
95.3 |
59.6 |
62.6 |
77.6 |
19.2 |
144 |
87.0 |
99.4 |
119 |
89.0 |
98.7 |
14.7 |
BLLOQ - Below the Lower Limit of Quantification, LOQ = 50 ng/mL
Table 6. Concentration of test substance (ng/mL) in male rat plasma following oral gavage administration of 50 mg/kg/day – last exposure group
Time (h) |
L05 |
L06 |
L07 |
L08 |
Mean |
SD |
144 |
76.8 |
188 |
54.6 |
163 |
121 |
64.9 |
144.083 |
67.4 |
195 |
56.4 |
136 |
114 |
64.8 |
144.25 |
59.6 |
235 |
55.1 |
133 |
121 |
84.0 |
144.5 |
65.1 |
338 |
60.2 |
158 |
155 |
130 |
145 |
184 |
735 |
163 |
273 |
339 |
268 |
146 |
565 |
1917 |
650 |
1216 |
1087 |
624 |
148 |
1837 |
3747 |
417 |
2341 |
2085 |
1375 |
150 |
1644 |
3247 |
1321 |
1170 |
1845 |
955 |
152 |
983 |
2081 |
1896 |
783 |
1436 |
648 |
156 |
341 |
791 |
337 |
1144 |
654 |
391 |
168 |
BLLOQ |
196 |
BLLOQ |
119 |
79 |
96.2 |
BLLOQ - Below the Lower Limit of Quantification, LOQ = 50 ng/mL
Table 1. Concentration of the substance (ng/mL) in male rat plasma following 5 mg/kg intravenous bolus administration
Time (h) |
J01 |
J02 |
J03 |
J04 |
Mean |
SD |
0.0167 |
7501 |
10146 |
6669 |
6182 |
7624 |
1767 |
0.083 |
4063 |
4506 |
3724 |
4244 |
4134 |
329 |
0.25 |
2225 |
2254 |
1914 |
1987 |
2095 |
170 |
0.5 |
969 |
1270 |
936 |
960 |
1034 |
158 |
1 |
504 |
604 |
437 |
507 |
513 |
68.6 |
2 |
294 |
364 |
258 |
298 |
303 |
44.1 |
4 |
152 |
191 |
171 |
171 |
171 |
16.1 |
6 |
118 |
135 |
103 |
115 |
118 |
13.1 |
8 |
95.5 |
113 |
96.4 |
93.0 |
99.5 |
9.29 |
12 |
76.9 |
64.9 |
54.4 |
63.1 |
64.8 |
9.26 |
24 |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ |
BLLOQ - Below the Lower Limit of Quantification, LOQ = 50 ng/mL
Description of key information
Following single IV (5 mg/kg) or oral (50 and 500 mg/kg) administration of CA5204 to male rats, the data indicate that CA5204A is a low clearance (CLz = 1.25±0.130 L/h/kg) compound that non-specifically distributes into tissues and is eliminated with a half-life of ca. 3.25 – 7.49 hours for the 5 mg/kg and 50 mg/kg dose groups and 10.1±2.30 hours for the 500 mg/kg dose group. A supraportional increase in systemic exposure (AUC0-∞) of CA5204A in male rat plasma was observed between 50 and 500 mg/kg. The oral bioavailability of CA5204A in male rat plasma for the 50 mg/kg (19.1-23.6%) and 500 mg/kg (132-159%) dose groups has been determined using the AUC0-t and should therefore be considered an underestimate of the absolute oral bioavailability. Following repeat oral administration to male rats, CA5204A predose concentrations in the plasma were approximately 2-fold greater than the LLOQ (50 ng/mL) and an increase (approximately 2-fold) in the mean CA5204A systemic exposure (AUC0-t) of the last exposure group was observed, compared to the mean CA5204A systemic exposure of the first group. CA5204A was found to be a substrate for P450 mediated metabolism across species when incubated with liver microsomes or recombinant human P450 enzymes and was also found to have a high affinity for binding to rat dog and human plasma proteins. Following 7 days repeated oral administrations of 50 mg/kg CA5204A to male rats, the AUC (measure of exposure) of the first (AUC0-∞) and last (AUC0-24) were similar and with the short plasma half-life (3.25-7.49 h) provides that CA5204A does not accumulate upon repeat dosing.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
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