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EC number: 947-917-0 | CAS number: -
- 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
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Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
- Objective of study:
- metabolism
- toxicokinetics
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.36 (Toxicokinetics)
- Version / remarks:
- 1988
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Version / remarks:
- 1984
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- Amines, N-C12–C14(even numbered)-alkyltrimethylenedi-, reaction products with chloroacetic acid
- Molecular formula:
- n.a. (UVCB substance)
- IUPAC Name:
- Amines, N-C12–C14(even numbered)-alkyltrimethylenedi-, reaction products with chloroacetic acid
- Reference substance name:
- Water
- EC Number:
- 231-791-2
- EC Name:
- Water
- Cas Number:
- 7732-18-5
- Molecular formula:
- H2O
- IUPAC Name:
- water
- Test material form:
- solid - liquid: aqueous solution
- Details on test material:
- - Name of test material: DOPA-Glycinate
Constituent 1
Constituent 2
- Radiolabelling:
- yes
Test animals
- Species:
- rat
- Strain:
- other: CD / Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Ltd., Sulzfeld, Germany
- Age at study initiation: 7 weeks (males), 9-12 weeks (females)
- Weight at study initiation: 228–252 g (males), 210–288 g (females)
- Fasting period before study: no
- Housing: individually
- Individual metabolism cages: no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5-8 d
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 55±15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- other: Oral - gavage (single administration: Group 1, 2 and 3; repeated administration: group 5); intravenous (single administration: group 4)
- Vehicle:
- other: Oral (group 1, 2, 3 und 5): 0.8 % aqueous hydroxypropyl-ethyl-cellulose gel; Intravenous (group 4): 0.9 % NaCl solution
- Duration and frequency of treatment / exposure:
- single oral administration: Group 1, 2 and 3
repeated oral administration: group 5; once daily for 13 d
single intravenous administration: group 4
Doses / concentrations
- Remarks:
- Doses / Concentrations:
30 mg/kg bw and 100 mg/kg bw of test substance (each dose contained 0.49 mg 14C-labelled test item/kg bw corresponding to a radioactive dose of 700 kBq/kg bw).
- No. of animals per sex per dose / concentration:
- Group 1 (low dose): 8 females
Group 2 (low dose): 4 males and 4 females
Group 3 (high dose): 4 males and 4 females
Group 4 (low dose): 8 females
Group 5 (repeated low dose): 4 females - Control animals:
- no
- Details on study design:
- Pilot study:
In order to determine the high dose level for the main study an orientating acute oral toxicity test and a preliminary excretion experiment to determine the relevance of excretion via expired air were carried out. Based on the results of these preliminary studies the following decisions were made for main study:
A high dose level of 100 mg/kg bw was used in the main study;
Excretion of test substance via expired air was significant and thus measured during main study. - Statistics:
- Pharmacokinetic evaluation of plasma data using program TopFit 2.11
Results and discussion
- Preliminary studies:
- The following no-effects levels were determined in an orientating experiment:
NOEL rat, i.v. = 125 mg/kg bw; NOEL rat, p.o = 400 mg/kg bw.
The administered radioactivity was distributed as follows: Approximately 55 %/19 % (p.o./i.v.) in the faeces, 6 %/23 % in urine, 0.6 %/0.9 % in cage wash, and 12 % (p.o.) in expired air. The mean of the highest plasma concentration was 0.04 %/0.25 % (p.o./i.v.). The fraction of radioactivity excreted in expired air indicated that this route of elimination is relevant.
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- 34% oral absorption
- Type:
- distribution
- Results:
- throughout the body, with the highest levels in the residual carcass, in the liver, the kidneys, and the adipose tissue
- Type:
- metabolism
- Results:
- mainly oxidation (hydroxylation), to a minor extent dehydrogenation and acetylation
- Type:
- excretion
- Results:
- excreted rapidly within 24 hours; main elimination pathway: via the faeces, followed by expired air and urine
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Oral absorption: The systemic bioavailability of 14C labelled test substance was 34 % following oral administration, as derived from the comparison of the AUC0–∞ (see Table A6.2- 2).
- Details on distribution in tissues:
- Radioactivity was distributed throughout the body, with the highest levels in the residual carcass, in the liver, the kidneys, and the adipose tissue. Nevertheless, distribution was quite uniform across all examined organs with no tissue storage in brain, heart, ovaries and spinal cord. There was no significant difference in the distribution of radioactivity in the tissues after single or repeated administration of 30 mg test substance/kg bw.
Results of tissue distribution are summarised in the Table A6.2- 3.
- Details on excretion:
- The vast majority of the administered radioactivity was excreted rapidly within 24 hours.
The main elimination pathway was via the faeces, followed by expired air and urine in all test groups. See Table A6.2- 1 for details.
After 168 hours approximately 60% of the radioactivity administered had been excreted via the faeces in the male and female animals, approximately 18% was excreted via expired air (approx. 15% in the males, 20% in the females), and approximately 9% was recovered in the urine. Less than 20% was found in organs and carcass.
There were no relevant differences in the mean radioactive recovery after 24 or 168 hours from urine and cage wash between the low, high, and repeated dose groups (see Table A6.2- 1).
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- In urine, the parent compounds N-C12 Gly, N’-C12 Gly, N’-C12 di Gly, C12 PDA and several metabolites were identified by mass spectrometry. Oxidation (hydroxylation) of the parent and some other metabolites like dehydrogenated and acetylated compounds, especially for C12 PDA, were identified. The most abundant compounds in urine were the oxidation products.
In plasma, only the unchanged parent compounds N-C12 Gly, N’-C12 Gly, N’-C12 di Gly, C12 PDA could be identified by mass spectrometry. For the radioactivity counting only N-C12 Gly, N’-C12 Gly were identified. The most abundant compounds in plasma were the parent substance N-C12 Gly and N’-C12 Gly.
In faeces, N-C12 Gly, N’-C12 Gly, N’-C12 di Gly, C12 PDA and several metabolites were identified by mass spectrometry. Oxidation (hydroxylation) of the parent and some other metabolites, like dehydrogenated and acetylated modifications, was demonstrated. The most abundant compounds in faeces were the oxidation products.
Any other information on results incl. tables
Toxic effects, clinical signs |
In the main experiment one male animal died prematurely and was found dead on test day 6. This death was not test item-related, but caused by a congested and blocked absorber for CO2determination. The faeces of all rats showed a normal consistency during the entire experimental period. No other effects were reported. |
Recovery of labelled compound |
Total recovery of administered radioactivity as determined in the excretion studies ranged from 97 to 103 % (rounded, seeTable A6.2-1). |
Pharmacokinetics |
After administration of 30 mg/kg bw (low dose) of [14C]-labeled test substancevia the oral and intravenous route the following toxicokinetic parameters were established: Plasma half-life: approx. 74 h both in the p.o. and i.v. group |
Table A6.2-1:Excretion: Mean recovery of radioactivity (%) after administration of [14C]-labelled test substance
|
Group 2: Single low dose |
Group 3: Single high dose |
Group 5: Repeated low dose |
||
|
Male |
Female |
Male |
Female |
Female |
Number of animals |
4 |
4 |
4 |
4 |
4 |
Urine (0–24 h) |
6.88 |
6.65 |
7.92 |
7.77 |
6.62 |
Urine (0–168 h) |
8.59 |
8.39 |
9.84 |
10.03 |
8.92 |
Faeces (0–24 h) |
51.06 |
51.72 |
49.03 |
44.01 |
42.35 |
Faeces (0–168 h) |
59.32 |
59.47 |
58.55 |
57.68 |
54.17 |
Expired air (0–24 h) |
10.13 |
12.74 |
9.85 |
13.00 |
7.84 |
Expired air (0–168 h) |
15.39 |
21.49 |
15.57 |
21.53 |
13.76 |
Cage wash (0–168 h) |
0.31 |
0.28 |
0.15 |
0.34 |
0.40 |
Carcass and organs |
n.e. |
13.33* |
n.e. |
n.e. |
19.22 |
Total |
|
102.96 |
|
|
96.47 |
Data expressed as mean % of total dose (dpm) administered ± standard deviation * Values derived from test group 1 with 8 female test animals administered orally a single low dose of test substance n.e.: not examined |
Table A6.2-2:Toxicokinetic parameters for [14C]-labelled test substance.
Dosage |
Route of administration |
Noncompartmental analysis |
|||||
Cmax# |
tmax# |
t1/2 |
AUC0-120 h |
AUC0-¥h |
AUC/dose## |
||
30 mg/kg bw |
p.o. |
47.5 |
6.00 |
76.62 |
2733.30 |
4126.83 |
6.87 |
|
i.v. |
606.5 |
- |
71.28 |
9304.88 |
12121.16 |
16.76 |
# Values obtained from the analytical results, all other values calculated by toxicokinetic analysis ## Dose in Bq/kg b.w. (mean values per group) i.v. intravenous administration p.o. oral administration |
Table A6.2-3:Distribution:Mean recovery of radioactivity (%) in organs at termination
|
Group 1: Single oral dose |
Group 4: Single intravenous dose |
Group 5: Repeated oral dose |
|
Female |
Female |
Female |
Number of animals |
8 |
8 |
4 |
Adipose tissue |
0.07 |
0.11 |
0.15 |
Brain |
0.02 |
0.07 |
0.02 |
Carcass |
12.13 |
19.06 |
17.72 |
Heart |
0.02 |
0.09 |
0.03 |
Kidneys |
0.17 |
0.75 |
0.22 |
Liver |
0.91 |
3.72 |
1.06 |
Ovaries |
0.01 |
0.05 |
0.02 |
Spinal cord |
0.00 |
0.01 |
0.00 |
Total |
13.33 |
23.86 |
19.22 |
Data expressed as mean % of total dose (dpm) administered ± standard deviation |
Figure A6.2-1:Proposed pathway of the metabolism of N-C12 Gly
see attached Image file
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): low bioaccumulation potential based on study results
The systemic bioavailability of 14C labelled DOPA-Glycinate was 34% following oral administration.
The substance was distributed throughout the body, with the highest levels in the residual carcass, in the liver, the kidneys, and the adipose tissue.
The plasma half-life was determined to be approx. 74 h.
The substance is mainly metabolised by oxidation (hydroxylation), and to a minor extent dehydrogenation and acetylation.
The vast majority of the administered radioactivity was excreted rapidly within 24 hours. The main elimination pathway was via the faeces, followed by expired air and urine. - Executive summary:
Absorption, distribution, metabolism and excretion of [14C]- DOPA-Glycinate (20% a.i.) were investigated in the rat according to the OECD test guideline 417. The test substance was administered orally by gavage at two single dose levels of 30 and 100 mg/kg bw, singly intravenous and orally at one repeated low dose level.
Upon oral administration, radioacitivity was predominantly eliminated via faeces (approx. 60 %) and via expired air (approx. 18 %). A lower proportion was excreted via urine (approx. 9 %) and less than 20 % of the administered dose was found in the carcass. No significant differences of absorption and elimination of test substance regarding high or low dose, repeated administration or sex could be indentified. The recovery of radioactivity was greatest in the residual carcass (12–19 %), followed by the liver (approx 4 %). In all other tissues the radioactive recovery was low (≤ 1.00 %) and quite uniformly distributed, with no tissue storage in brain, heart, ovaries and spinal cord. There was no relevant difference in the tissue distribution of radioactivity between animals treated orally or intravenously with a single or repeated dose of the test substance. The elimination half-life was approx. 74 hours both in the p.o. and i.v. group.
The systemic bioavailability, assessed by comparison of plasma radioactivity after oral and intravenous administration, was 34%.
In plasma, only parent substances but no transformation products could be identified. A first-pass effect following intestinal absorption is therefore unlikely. In urine and faeces, parent substances as well as transformation products were detected. Metabolites in both urine and faeces were characterised by oxidation (hydroxylation) of the parent and some other metabolites like dehydrogenated and acetylated compounds. The most abundant compounds in urine were the oxidation products.
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