Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
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: 700-327-5 | CAS number: 1061328-86-6
- 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
Exposure related observations in humans: other data
Administrative data
- Endpoint:
- exposure-related observations in humans: other data
- Type of information:
- other: study addressed: chelating agent HBED (precursor of Fe(Na)HBED)
- Adequacy of study:
- supporting study
- Study period:
- 1994
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well documented publication
Data source
Reference
- Reference Type:
- publication
- Title:
- Preliminary Results from a Phase I Clinical Trial of HBED
- Author:
- Grady, R.W., Salbe, A.D., Hilgartner, M. W., Giardina, P. J.
- Year:
- 1 994
- Bibliographic source:
- The Development of Iron Chelators for Clinical Use, Raymond J. Bergeron, Gary M. Brittenham, 1994, CRC Press, ISBN:0849386799
Materials and methods
- Type of study / information:
- A pharmacokinetic study was performed in 4 patients (2 males, 2 females) within the scope of efficacy study on HBED as drug used in chelation therapy.
- Endpoint addressed:
- basic toxicokinetics
Test guideline
- Qualifier:
- no guideline required
- Principles of method if other than guideline:
- HBED was tested in humans for its efficacy in treatment of transfusion-induced iron overload in patients with β-thalassemia. Patients were admitted to a Clinical Research Centre for 24 days, during which time they consumed a low iron diet and provided 24-h specimens of urine and stool. DFO (desferrioxamine) (60 mg/kg) was infused subcutaneously over 8 h on days 5 to 10, with HBED being given orally on days 15 to 20. A stool marker was taken orally before the first and the last dose of each drug. Transfusions were given on days 1 and 11 to ensure that the haemoglobin concentration would be the same at the time of administration of each drug. Routine laboratory tests (LT, blood profiles, serum chemistries, and urinalyses) were done approximately every 3 days.
- GLP compliance:
- no
Test material
- Reference substance name:
- N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N' diacetic acid
- IUPAC Name:
- N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N' diacetic acid
- Reference substance name:
- 35369-53-0
- Cas Number:
- 35369-53-0
- IUPAC Name:
- 35369-53-0
- Details on test material:
- Pure compound in 250 mg gelatin capsules
Constituent 1
Constituent 2
Method
- Ethical approval:
- other: According to FDA permission no IND#36776
- Details on study design:
- HBED was tested in humans for its efficacy in treatment of transfusion-induced iron overload in patients with β-thalassemia. Patients were admitted to a Clinical Research Centre for 24 days, during which time they consumed a low iron diet and provided 24-h specimens of urine and stool. DFO (desferrioxamine) (60 mg/kg) was infused subcutaneously over 8 h on days 5 to 10, with HBED being given orally on days 15 to 20. A stool marker was taken orally before the first and the last dose of each drug. Transfusions were given on days 1 and 11 to ensure that the haemoglobin concentration would be the same at the time of administration of each drug. Routine laboratory tests (LT, blood profiles, serum chemistries, and urinalyses) were done approximately every 3 days. Special studies (eye examinations, audiograms, and electrocardiograms) were done on days 1-3, 14 and 22-24. A pharmacological study was undertaken upon giving the first dose of HBED. Complete physical examinations were done at admission, before giving HBED and before discharge. Subjective questionnaires were filled out by the patients after each drug treatment.
- Exposure assessment:
- measured
- Details on exposure:
- TYPE OF EXPOSURE: oral
TYPE OF EXPOSURE MEASUREMENT: Personal sampling: urine, blood, stool / other: eye examinations, audiograms, electrocardiograms, physical examinations
EXPOSURE LEVELS: The fisrt two patients were given HBED at a dose of 40 mg/kg divided t.i.d. As these patients experienced no difficulties, a permission from FDA was to increase the dose to 80 mg/kg in subsequent patients.
EXPOSURE PERIOD: day 15 to 20
POSTEXPOSURE PERIOD: 4 days
DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: not applicable
Results and discussion
- Results:
- HBED caused an increase in both urinary and faecal iron excretion, with faecal excretion accounting for more than 50% of the total in three of the patients. Upon increasing the dose of HBED from 40 to 80 mg/kg, total iron excretion increased from 11.4% to 16.6%. HBED was significantly less effective than predicted by the animal studies, iron balance ranging from 28 to 48%. While doubling the dose of drug caused an increase in the relative amount of iron excreted, the change was marginal in terms of iron balance. On the other hand, HBED did cause an increase in both urinary and faecal excretion of iron, suggesting that increasing the gastrointestinal absorption of this drug should enhance its efficacy.
Any other information on results incl. tables
TABLE 2 Net Iron Excretion in Response to DFO ami HBED
TABLE 3 Iron BaIance in Response to DFO and HBED DFO HBED
aFe-Ex -tolal iron excreted, bFe-Tx - iron received in the form of transfused erythrocytes. cIron excreted as a percentage of that received.
|
Applicant's summary and conclusion
- Conclusions:
- In summary, HBED has proven to be orally effective, inducing iron excretion in both urine and stool. The safety of HBED has been established, the patients experiencing no adverse side effects.
- Executive summary:
In summary, HBED has proven to be orally effective, inducing iron excretion in both urine and stool. The safety of HBED has been established, the patients experiencing no adverse side effects. Zinc excretion may be slightly enhanced in response to HBED, but not to levels considered to be toxic. Finally, despite the length of the hospital stay, the patients were enthusiastic about the study and have encouraged others to participate,
In this trial, DFO caused significantly more iron to be excreted than would have been predicted on the basis of serum ferritin levels and past compliance with DFO therapy. This illustrates the danger of using individual serum ferritin values as indicators of body iron load and suggests that serum ferritin levels can be normalized much faster than iron can be removed from the body, Thus, it is suggested that patients whose serum ferritin levels have been reduced to less than 1000 ng/ml be maintained on aggressive DFO therapy until their iron excretion shows a concomitant decrease. Routine measurement of urinary iron excretion should be considered an essential facet of good clinical management in cases of β-thalassemia.
Finally, four additional patients will be given HBED at a dose of 80 mg/kg divided t.i.d. If their levels of iron excretion are not greater than those reported here, they will either increase the dose of HBED to 120 mg/kg or discontinue the study until a prodrug such as the dimethyl ester (dmHBED) is available.
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.