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EC number: 944-549-2 | 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
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics, other
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Details on absorption:
- Oral absorption:
In the gastrointestinal tract proteins and polypeptides are broken down into a mixture of subunits that are sufficiently small for absorption (i.e. amino acids , di-and tripeptides). Degradation of peptides within the lumen of the gastrointestinal tract may be due to instability in an acidic environment, metabolism by digestive enzymes or luminal microorganisms. Proteolysis starts in the stomach in the presence of pepsin and continues throughout the intestine. Lumenal degradation of peptides is due to exposure to enzymes released from the the pancreas into the intestine (Hamman et al. 2005). Insulin has been shown to be completely inactivated within 3 minutes in gastric fluids from pigs, and in rats less than 1% of insulin was found to be absorbed after oral administration (Smart et al. 2014). The major problem for therapeutic oral insulin administration, besides proteolysis in the stomach and the small intestine, is that there are no selective insulin transport mechanisms across the gut wall and the epithelial cells of the intestinal tract normally do not transport macromolecules. Therefore, even if insulin is applied directly to the gut, extremely high doses are required to achieve at least some measurable insulin absorption (Heinemann et al 2001).
Thus, due to the structural similarities, the absorption of insulin aspart precursor and the read-across source substances from oral exposure may be considered to be minute, which is expected very much to reduce any toxic potential from oral exposure.
Dermal absorption:
Insulin aspart precusor and the read-across source substances are large proteinaceous molecule and absorption through the skin is expected to be low. Skin is generally considered as a very effective barrier for larger molecules such as polypeptides and proteins. For smaller molecules it has been shown that dermal penetration and absorption has a steep decline when the molecular size of a chemical exceeds 500 Dalton (Bos et al., 2000; Heinemann et al., 2001). An absorption at a very low percentage of insulin has been observed in hairless mice when applying an electrcial potential across the skin (iontophoresis) with the aim of promoting the skin penetration (Heinemann et al. 2001). However, under normal conditions, systemic uptake from dermal exposure to insulin and similar proteins at a molecular size of about 6000 Dalton is considered to be very low / insignificant.
Inhalational absorption:
Heinemann et al. (2001) reviewed human data on the relative biopotency of insulin from inhalational exposure compared to subcutaneous exposure. Overall it was concluded that when using optimal conditions for pulmonary uptake a relative potency of about 10% could achieved from inhalational exposure. Thus, such an overall absorption rate may be considered as a valid assumption for both insulin aspart precursor and the read-across source substances. - Details on excretion:
- T1/2 in plasma of insulin aspart of 22 minutes and 76 minutes have been measured in rats and humans, respectively (Novo Nordisk 1998)
- Details on metabolites:
- No studies regarding identification of metabolites of inuslin aspart have been conducted. As for human insulin a fast degradation of insulin aspart into inactive fragments is expected. The amino acids from the substance is expected to take part in the general metabolic pool of the body (Novo Nordisk 1998).
- Conclusions:
- For human insulin and insulin aspart the oral and demal absorption is considered negligible, because of degradation of the protein in the gastrointestinal tract and due to lack of dermal penetration and absorption of the large, proteinaceous molecule.
From human experiments for the development of inhalation therapy with insulin a relative absorption compared to s.c. injection of 10% has been found.
T1/2 in plasma of insulin aspart of 22 minutes and 76 minutes have been measured in rats and humans, respectively.
No studies regarding identification of metabolites of inuslin aspart have been conducted. As for human insulin, insulin aspart is expected to undergo fast degradation into inactive fragments. The amino acids from the substance is expected to take part in the general metabolic pool of the body. - Executive summary:
For human insulin and insulin aspart the oral and demal absorption is considered negligible, because of degradation of the protein in the gastrointestinal tract and due to lack of dermal penetration and absorption of the large, proteinaceous molecule.
From human experiments for the development of inhalation therapy with insulin a relative absorption compared to s.c. injection of 10% has been found.
T1/2 in plasma of insulin aspart of 22 minutes and 76 minutes have been measured in rats and humans, respectively.
No studies regarding identification of metabolites of inuslin aspart have been conducted. As for human insulin, insulin aspart is expected to undergo fast degradation into inactive fragments. The amino acids from the substance is expected to take part in the general metabolic pool of the body.
- Endpoint:
- basic toxicokinetics, other
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods
- Objective of study:
- other: receptor binding
- GLP compliance:
- no
- Preliminary studies:
- From insulin receptor binding assays (Novo Nordisk 2015) the following relative binding was observed for insulin APIs and the various insulin intermediates:
Human insulin (API, two chains): 100 %
Human insulin methyl ester (two chains): 108 %
DesB 30 human insulin (two chains) : 133 %
X14DesB30 (S3, two chains): not examined Insulin aspart (API, S1, two chains): 100% %
Insulin aspart ethyl ester (two chains): 103%
Insulin aspart precursor (T, one chain) : 0.03 %
MI3 (S2, one chain): 0.22%
These data indicate that receptor binding affinity is lost when the two amino acids chains are linked together in one chain,
most probably due to a great change in the steric form of the molecule. - Conclusions:
- Human insulin receptor affinity of insulin aspart precurser relative to the API, insulin aspart, was found to be 0.03% [0.02 to 0.06]. Results are given as weighted means of three independent experiments with the corresponding 95% confidence intervals
- Executive summary:
Human insulin receptor affinity of insulin aspart precurser relative to the API, insulin aspart, was found to be 0.03% [0.02 to 0.06]. Results are given as weighted means of three independent experiments with the corresponding 95% confidence intervals.
Referenceopen allclose all
From insulin receptor binding assays (Novo Nordisk 2015) the following relative binding was observed for insulin APIs and the various insulin intermediates:
Human insulin (API, two chains): 100 %
Human insulin methyl ester (two chains): 108 %
DesB 30 human insulin (two chains) : 133 %
X14DesB30 (S3, two chains): not examined
Insulin aspart (API, S1, two chains): 100 %
Insulin aspart ethyl ester (two chains): 103%
Insulin aspart precursor (T, one chain) : 0.03 %
MI3 (S2, one chain): 0.22%
These data indicate that receptor binding affinity is lost when the two amino acids chains are linked together in one chain,
most probably due to a great change in the steric form of the molecule.
Description of key information
Absorption
Oral absorption: In the gastrointestinal tract proteins and polypeptides are broken down into a mixture of subunits that are sufficiently small for absorption (i.e. amino acids, di-and tripeptides). Degradation of peptides within the lumen of the gastrointestinal tract may be due to instability in an acidic environment, metabolism by digestive enzymes or luminal microorganisms. Proteolysis starts in the stomach in the presence of pepsin and continues throughout the intestine. Lumenal degradation of peptides is due to exposure to enzymes released from the the pancreas into the intestine (Hamman et al. 2005). Insulin is completely inactivated within 3 minutes in gastric fluids from pigs, and in rats less than 1% of insulin was found to be absorbed after oral administration (Smart et al. 2014). The major problem for therapeutic oral insulin administration, besides proteolysis in the stomach and the small intestine, is that there are no selective insulin transport mechanisms across the gut wall and the epithelial cells of the intestinal tract normally do not transport macromolecules. Therefore, even if insulin is dosed directly into the gut, extremely high doses are required to achieve at least some measurable insulin absorption (Heinemann et al 2001).
Thus, due to the structural similarities, the oral absorption of insulin aspart precursor and the read-across source substances may be considered to be minute, which is expected very much to reduce any toxic potential from oral exposure.
Dermal absorption: Insulin aspart precusor and the read-across source substances are large proteinaceous molecule and absorption through the skin is expected to be low. Skin is generally considered as a very effective barrier for larger molecules such as polypeptides and proteins. For smaller molecules it has been shown that dermal penetration and absorption has a steep decline when the molecular size of a chemical exceeds 500 Dalton (Bos et al., 2000; Heinemann et al., 2001). An absorption at a very low percentage of insulin has been observed in hairless mice when applying an electrical potential across the skin (iontophoresis) with the aim of promoting the skin penetration (Heinemann et al. 2001). However, under normal conditions, systemic uptake from dermal exposure to insulin and similar proteins at a molecular size of about 6000 Dalton is considered to be very low / insignificant.
Inhalational absorption: Heinemann et al.(2005) reviewed data on the relative biopotency of insulin from inhalational exposure compared to subcutaneous exposure. Overall, it was concluded that when using optimal conditions for pulmonary uptake a relative potency of about 10% could achieved from inhalational exposure. Thus, such an overall absorption rate may be considered as a valid assumption for both insulin aspart precursor and the read-across source substances.
Insulin Receptor binding
Human insulin receptor affinity of insulin aspart precurser relative to the API, insulin aspart, was found to be 0.03% [0.02 to 0.06]. Results are given as weighted means of three independent experiments with the corresponding 95% confidence intervals.
Key value for chemical safety assessment
- Absorption rate - oral (%):
- 0
- Absorption rate - dermal (%):
- 0
- Absorption rate - inhalation (%):
- 10
Additional information
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.
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