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EC number: 616-017-7 | CAS number: 7377-08-4
- 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, other
- Type of information:
- other: Expert statement
- Adequacy of study:
- weight of evidence
- Study period:
- 29 April 2019
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- other: Expert statement
- Objective of study:
- other: Toxicokinetics expert statement
- Qualifier:
- no guideline required
- GLP compliance:
- no
- Specific details on test material used for the study:
- Substance name: 4-Aminobenzoyl-b-alanine
CAS No.: 7377-08-4
EC No.: 616-017-7
Relevant physico-chemical properties:
Molecular weight: 208.22
Water solubility: 11.75 g/L (Meluso A., 2018)
Octanol-water -1.19 (Meluso A., 2018)
partition coefficient
(log Pow):
Vapour pressure: 9.70E-05 Pa (Urbani M., 2018) - Details on absorption:
- ORAL ROUTE
The absorption of 4-Aminobenzoyl-b-alanine was calculated using the relative radioactivity found in the urine following oral and i.v. administrations (see separate IUCLID summary for i.v.) and was found to be 14%. Strictly speaking, this is oral bioavailability rather than actual absorption via the GI tract. Therefore, in this case, 14% oral bioavailability would indicate > 14% GI tract absorption. However, it is not possible to determine the actual absorption through the lining of the GI tract, as this would require knowledge of the extent of any ABA transport to the gut via the liver before any N-acetylation or systemic absorption occurred and ABA that was never absorbed and reached the colon. Information on the amount of ABA detected in the faeces is not available to make this estimation.
INHALATION ROUTE
4-Aminobenzoyl-b-alanine is predicted to have similar levels of absorption to the oral route (i.e.> 14%), since it has moderately good solubility in water. Assuming particles of respirable size were inhaled, it is reasonable to assume that complete absorption of the substance would eventually occur (dependent on the extent of any metabolism in the lining of the lungs), as unlike the GI tract, the residence time in the alveoli could be longer. The rate of absorption (amount per day) is however, difficult to determine.
DERMAL ROUTE
4-Aminobenzoyl-b-alanine is predicted to have low absorption via the dermal route, primarily based on its very low log Pow value of -1.19, indicative of a low likelihood of passage through the lipid layer in the skin. - Details on distribution in tissues:
- Maximum plasma levels of ABA, NABA and radioactivity were reached 15 minutes after dosing. Values were 0.0034, 0.0116 and 0.0163 micromol/mL respectively. Given their water soluble nature and low log Pow, they would not be expected to accumulate in organs.
- Details on excretion:
- Plasma radioactivity declined quickly and was below the limit of detection 24 hrs after dosing. Most of the radioactivity that was excreted in urine was associated with the metabolite NABA (11.5% of the dose). Given that the oral absorption (or strictly speaking bioavailability) was assigned as 14% of the dose in the review, this NABA would equate to metabolism of at least 80% of the ABA reaching the systemic circulation. The rapid drop in radioactivity in the plasma and its detection in urine indicates that clearance of the ABA is via its metabolite NABA and is rapid and extensive.
- Metabolites identified:
- yes
- Details on metabolites:
- The ratio of the maximum plasma levels of ABA to NABA after only 15 minutes from dosing was 0.0034:0.0116, which indicates 77% metabolism of the absorbed ABA to its N-acetylated metabolite NABA. Based on the result of the i.v. test (see separate IUCLID entry) which showed 80% of injected ABA remained intact in the urine, this is strongly suggestive of a high degree of first-pass metabolism via the oral route.
- Conclusions:
- ABSORPTION
Oral absorption is predicted to occur to a moderate degree.
Absorption via inhalation route is predicted to occur to a low-moderate extent (for respired particles)
4-Aminobenzoyl-b-alanine is predicted to have low absorption via the dermal route.
DISTRIBUTION
There is minimal available information relating to distribution. Given the water -soluble nature and negative log Pow value, it is predicted that accumulation in organs is unlikely.
METABOLISM
It is predicted that absorbed ABA will be rapidly and extensively metabolised to N-acetyl-4-aminobenzoyl-5-alanine (NABA), via a first-pass effect.
EXCRETION
It is predicted that 4-Aminobenzoyl-b-alanine would be rapidly and extensively excreted via urine, predominantly as its metabolite NABA. - Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Objective of study:
- toxicokinetics
- Principles of method if other than guideline:
- A single oral dose of radiolabelled ABA was given to rats. Blood samples were collected at 15 min and 2 and 6 hours after dosing. Urine and faeces samples were collected from 0-6, 6-12 and 12-24 hrs after dosing. Plasma and urine levels of ABA and its metabolite NABA were determined using HPLC. The radioactivity was determined using liquiid scintillation counting.
- GLP compliance:
- not specified
- Radiolabelling:
- yes
- Species:
- rat
- Strain:
- not specified
- Sex:
- not specified
- Route of administration:
- oral: unspecified
- Vehicle:
- not specified
- Duration and frequency of treatment / exposure:
- Single dose
- Dose / conc.:
- 64 mg/kg bw (total dose)
- No. of animals per sex per dose / concentration:
- Not specified
- Control animals:
- not specified
- Details on dosing and sampling:
- A single oral dose of 64 mg/kg was given. Blood samples were taken at 15 minutes, 2 and 6 hrs after dosing. Urine and faecal samples were collected from 0-6, 6-12 and 12-24 hrs after dosing.
- Type:
- absorption
- Results:
- 14% as calculated using the radioactivity found in the urine following oral and i.v. administrations (see seperate summary for iv)
- Type:
- distribution
- Results:
- Maximum plasma levels of ABA, NABA and radioactivity were reached 15 minutes after dosing. Values were 0.0034, 0.0116 and 0.0163 micromol/ml respectively.
- Type:
- metabolism
- Results:
- The ratio of the maximum plasma levels of ABA to NABA after only 15 minutes from dosing, was already 0.0034:0.0116, which indicates 77% metabolism of the dosed ABA to its N-acetylated metabolite NABA.
- Type:
- excretion
- Results:
- Plasma radioactivity declined quickly and was below the limit of detection 24 hrs after dosing.
- Details on absorption:
- The 14% oral absorption stated in the review of the study is assumed to refer to bioavailability rather than GI tract absorption, which is different. Bioavailability in pharmacology (which is the context of the review) relates to a comparison of the amount of a substance in the plasma when administered via i.v. against the plasma concentration for the same dose but given orally. In this case, the comparison has used levels in urine instead of plasma, after 24 hrs. In this case therefore, 14% bioavailability would indicate a > 14% GI tract absorption, with the balance potentially excreted from the liver back to the lower GI tract via bile and/or passing unabsorbed to ultimately be excreted in faeces.
- Details on distribution in tissues:
- Insufficient information available
- Details on excretion:
- Most of the radioactivity that was excreted in urine, was associated with the metabolite NABA (11.5% of the dose). Given that the oral absorption was assigned as 14% of the dose in the review, this NABA would equate to metabolism of at least 80% of the ABA reaching the systemic circulation . The rapid drop in radioactivity in the plasma and its detection in urine, indicates that clearance of the ABA is via its metabolite NABA and is rapid and extensive.
- Metabolites identified:
- yes
- Details on metabolites:
- The metabolite is N-acetyl-4-aminobenzoyl-5-alanine (NABA).
- Conclusions:
- Orally dosed ABA was rapidly absorbed (most likely) from the upper GI tract, as indicated by the plasma Tmax of only 15 minutes. The extent of oral absorption was at least 14% based on comparison of urine for oral and i.v. tests. The majority (approx 80%) of the absorbed ABA was rapidly metabolised to N-acetyl-4-aminobenzoyl-5-alanine (NABA) as indicated by the relative Tmax plasma concentrations after 15 minutes. The rapid drop in radioactivity in the plasma and its detection in urine, indicates that ABA is unlikely to be distributed to body tissues and that clearance of the ABA via its metabolite NABA is rapid and extensive.
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Objective of study:
- toxicokinetics
- Principles of method if other than guideline:
- A single intravenous dose of radiolabelled ABA was given to rats. Blood samples were collected at 15 min and 2 and 6 hours after dosing. Urine and faeces samples were collected from 0-6, 6-12 and 12-24 hrs after dosing. Plasma and uring levels of ABA and its metabolite NABA were determined using HPLC. The radioactivity was determined using liquiid scintillation counting.
- GLP compliance:
- not specified
- Radiolabelling:
- yes
- Species:
- rat
- Strain:
- not specified
- Sex:
- not specified
- Route of administration:
- intravenous
- Vehicle:
- not specified
- Duration and frequency of treatment / exposure:
- Single dose
- Dose / conc.:
- 64 mg/kg bw/day (actual dose received)
- Control animals:
- no
- Positive control reference chemical:
- No
- Type:
- absorption
- Results:
- Not relevant as intravenous
- Type:
- distribution
- Results:
- No details of any tissue distribution
- Type:
- excretion
- Results:
- Plasma radioactivity decline quickly to below LoD within 6 hours. The majority of the radioactivity dosed was associated with ABA (approx 80% of dose) in the urine.
- Type:
- metabolism
- Results:
- The majority of ABA was not N-acetylated to NABA, as 80% of the dose was found in the urine, demonstrating that N-acetylation occurs in the liver during first pass and in the lining of the GI tract, both of which are by-passed by i.v. administration.
- Details on distribution in tissues:
- No information on distribution was provided in the review. However, given the high %dose in the urine, it does not indicate that ABA distributes widely around the body into tissues.
- Details on excretion:
- A significant amount (80%) of i.v. dose ABA goes to the kidneys and is excreted into urine, in this case.
- Conclusions:
- When ABA is directly dosed into the systemic circulation via i.v. administration, it is rapidly excreted via the kidneys into urine. In the equivalent oral test, the result was almost opposite (i.e. 80% of absorbed ABA was found as NABA in urine). The result of this study shows the strong impact of N-acetylation on the ABA when administered orally and then exposed to N-acetyltransferases present in liver and gut lining, both of which would be bypassed to a significant degree by the i.v. administration. This would also support an argument for significant acetylation of ABA to NABA in human skin resulting in the systemic circulation being primarily exposed to NABA, rather than ABA.
Referenceopen allclose all
Description of key information
ABSORPTION
Oral absorption is predicted to occur to a moderate degree.
Absorption via inhalation route is predicted to occur to a low-moderate extent (for respired particles)
4-Aminobenzoyl-b-alanine is predicted to have low absorption via the dermal route.
DISTRIBUTION
There is minimal available information relating to distribution. Given the water -soluble nature and negative log Pow value, it is predicted that accumulation in organs is unlikely.
METABOLISM
It is predicted that absorbed ABA will be rapidly and extensively metabolised to N-acetyl-4-aminobenzoyl-5-alanine (NABA), via a first-pass effect.
EXCRETION
It is predicted that 4-Aminobenzoyl-b-alanine would be rapidly and extensively excreted via urine, predominantly as its metabolite NABA.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
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