Iotroxic acid

Endpoint summary

Description of key information

In accordance with REACH Annex XI, section 1.2, conducting a test for skin sensitization is scientifically not necessary since reliable and relevant human and animal data are available, which are justified in an expert statement (Hofmeister R., 2017: Assessment of the skin sensitization potential of Iotroxic acid (CAS 51022-74-3)). Based on the outcome of the expert statement, Iotroxic acid (target substance) is unlikely to be a significant skin sensitizer and the criteria for classification are not met.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Iotroxic acid (CAS 51022-74-3) is the contrast-enhancing component in the liver-specific, iodinated X-ray contrast medium Biliscopin® presented as its dimeglumine salt (meglumine iotroxate; CAS 68890-05-1) in the drug product. After intravenous administration, Biliscopin is secreted actively by the hepatocyte. Because of its high hepatocellular transport rate, it leads rapidly to high-grade contrast density in the intra-hepatic and extra-hepatic biliary ducts, as well as in the gall bladder. Only when the maximum transport capacity of the liver is exceeded, any appreciable renal elimination occurs. The first marketing authorization for Biliscopin was granted in Germany in September 1977 and the first launch was in November 1977 in Germany. Currently, the contrast agent is marketed by Bayer AG worldwide in more than 35 countries. According to Periodic Safety Update Reports (PSURs) routinely prepared by Bayer AG for marketed products, the number of bottles sold worldwide indicate that the number of patients who receive Biliscopin within one year are in the range of 50,000 to 60,000. (PSUR Biliscopin) Thus, taking the 40 years of market presence and the cumulated high number (ca. 2 million) of procedures / administrations of Biliscopin to patients into account, there is a huge clinical experience with regard to the safety of Iotroxic acid and its dimeglumine salt in patients and in physicians or technical personnel who handle this compound immediately before, during and after the diagnostic procedures.

 

Animal and in vitro data on local tolerance and skin sensitization

In the context of the development of Biliscopin (containing Iotroxic acid as the contrast enhancing component) nonclinical (toxicological) studies conducted in-house comprised acute and repeat-dose toxicity studies (2-3-week studies) in rats and dogs, genotoxicity studies, local tolerance as well as reproductive toxicity studies. Most studies were performed in the 1970’s according to the standards valid at that time, and no additional, relevant nonclinical safety studies were performed in-house since then. Local tolerance studies after single intravenous or intra-arterial injection of the highly concentrated sodium- and meglumine mixed salt formulation of Iotroxic acid in rabbits did not reveal any local symptoms of intolerance. After a single intramuscular administration slight to moderate signs of local irritation were noted in this animal species. No in vivo animal studies or in vitro studies on the skin sensitization potential of Iotroxic acid and its dimeglumine salt were performed.

 

Human data on skin sensitization

Biliscopin – as all other iodine-containg X-ray contrast media – is known to occasionally induce allergy-like anaphlactoid / hypersensitivity reactions, however only after intravenous administration to patients resulting in a maximum systemic exposure to the compound. Such adverse reactions commonly affecting the skin are reported as transient itching of the skin, angioedema, flush, erythema, urticaria, pruritus and exanthema. (Product Information for Biliscopin for Infusion) However, these reversible side effects indicating skin disorders after maximum systemic exposure (due to intravenous administration) of the dimeglumine salt of Iotroxic acid cannot be used to conclude on the skin sensitization potential of this compound in humans after direct contact with the skin. The clinical risk assessment with regard to the skin sensitization potential of Iotroxic acid and its dimeglumine salt after direct contact with the human skin can nevertheless be based on the broad clinical experience with Biliscopin, when focusing on reported side effects after extravasation or inadvertent paravenous administration of the contrast agent. According to the Product Information for Biliscopin, extravasation of Biliscopin gives rise to transient local pain and edema, and in rare cases also more severe tissue reactions are

described. Inadvertent paravenous administration of Biliscopin can cause transient pain, but experience has shown that it is not followed by serious tissue reactions.

These observations are in line with the findings obtained in nonclinical local tolerance studies conducted in experimental animals. Due to the fact that Biliscopin (containing Iotroxic acid as the contrast-enhancing component) is marketed since 40 years and frequently used and handled by physicians and/or technical personnel during diagnostic procedures in patients, a query on observed and reported local skin reactions after dermal contact in the context of procedural complications (application and instillation site reactions) and skin and subcutaneous tissue disorders have

been initiated while using the adverse event data base of Bayer AG.

The retrieval criteria were based on the following MedDRA terms:

 

General disorders and administration site conditions

- High Level Terms (HLT): Application and instillation site reactions

- High Level Group Terms (HLGT): Tissue disorders (NEC [not elsewhere classified])

Injury, poisoning and procedural complications

- HLGT: Administration site reactions

- HLGT: Exposures, chemical injuries and poisoning

- HLGT: Medication errors and other product use errors and issues

- HLGT: Procedural related injuries and complications (NEC)

 

Skin and subcutaneous tissue disorders

- HLT: Skin injuries (NEC)

 

With respect to the received query on Biliscopin and its potential to act as skin sensitizing agent, when directly exposed to the skin of workers at the production, during transport and during administration by physicians and others, there were no cases found in the adverse event database.

 

Assessment and overall conclusion

Overall there is proven broad experience related to the safe diagnostic use of Iotroxic acid and its dimeglumine salt and there is no evidence of skin reactions after direct contact of this compound with the human skin indicating a skin sensitizing potential of this compound. Therefore, based on the available reliable and relevant human data, the assessment of the skin sensitization potential (hazard identification) is possible. Based on the available data in the clinical use Iotroxic acid is unlikely to be a significant skin sensitizer and the criteria for classification are not met.

 

In line with REACH Annex XI, section 1.2 conducting a test on skin sensitization is therefore scientifically not necessary.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data, no classification for skin sensitization is warranted for the target substance.