Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: toxicokinetic assessment based on all available information
Adequacy of study:
key study
Study period:
February-March 2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: expert assessment of toxicokinetic properties based on all available information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The toxicokinetic assessment of the test item was performed based on all available information, including structural and physico-chemical properties of the substance and the results of available toxicological studies.
GLP compliance:
no

Test material

Constituent 1
Test material form:
liquid: viscous
Details on test material:
- Name of test material: Reaction product of 4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxypropane and aqueous phosphoric acid, 2-butoxyethanol, 2-(dimethylamino)ethanol
- Trade name: Uradil DD80
- State of aggregation: Colourless to light yellow high viscous liquid
- Batch: 616F-2072
- Density: 1.3 Pa.s
- Purity: 97%
- Water content: 0.3 w/w%
- Residual solvent: 2.7 w/w%
- Test item storage: At room temperature
- Stable under storage conditions until: 31 December 2017 (expiry date). After QC check executed in December 2017 the renewed expiry dateis 1 July 2018. This renewed expiry dated is cited in study reports of studies performed after 31 December 2017.

Radiolabelling:
no

Test animals

Species:
other: not applicable, no animal study performed

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
The derived absorption values are 100% for oral and respiratory absorption and 50% for dermal absoprtion.
Type:
distribution
Results:
Distribution through the body is expected; some degree of accumulation in adipose tissue cannot be excluded.
Type:
metabolism
Results:
Glucuronidation at the terminal hydroxyl groups is possible.
Type:
excretion
Results:
Glucuronidated metabolites may be eliminated with urine; biliary and fecal excretion is also possible.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on signs of systemic toxicity in the available 28-day study with developmental/reproductive toxicity screening, the substance is absorbed by oral route. The default 100% oral absorption is assumed for risk assessment purposes.
The test item is not volatile (vapour pressure < 0.0015 Pa), and based on the aggregation state of the substance (highly viscous liquid) it is not likely that the substance can reach the nasopharyngeal region or subsequently the tracheo/bronchial/pulmonary region via inhalation of vapour. However, the default value of 100% is assumed for respiratory absorption for risk assessment puprposes. If a liquid reaches the tracheobronchial region, it generally would readily diffuse/dissolve into the mucus lining of the respiratory tract. For highly apolar constituents of the test item absorption may be limited due to their low water solubility and high Log Pow; however, more water-soluble constituents may be readily absorbed. Furthermore, as the substance is a surface active compound, its absorption may be enhanced due to micellar solubilisation.
the test item is a liquid which can potentially be taken up across the skin. According to the criteria given in the REACH Guidance, a default value of 100% dermal absorption should be used unless MW >500 and log Pow <-1 or >4, in which case a value of 10% skin absorption should be chosen.1 While the weighted-average molecular weight of the main identified constituents of the test item is above 500 g/mol (i.e. 624 g/mol), the log Pow of its constituents varies significantly (from < 0.3 to 7.2). It thus needs to be considered that at least part of the test item may be capable of penetrating the skin. Furthermore, the substance is surface-active, which can enhance the potential dermal uptake. However, the main fraction of the substance is constituted by substances with high molecular weight (72% of the total mass percentage constituted by substances with molecular weight in a range of 394-952 g/mol, 21% by substances with molecular weight > 1000 g/mol). Based on this, the main fraction of the compound may be too big to penetrate the skin. Therefore as a worst-case the value of 50% is assumed for dermal absorption
Details on distribution in tissues:
Based on observed effects in the available 28-day toxicity study, upon uptake via gastrointestinal tract the substance is transported to liver where it is probably (partially) metabolized. Based on developmental effects observed in the same study, at least a part of the substance and/or its metabolites can also be distributed to other organs and tissues by systemic circulation. Based on high molecular weight and high log Pow of some components, some degree of accumulation in adipose tissue cannot be excluded.
Details on excretion:
Biliary and fecal excretion of some constituents may be expected to occur based on the molecular weight and high log Pow of the substance. Based on the the available toxicity results, it is also feasible to assume that at least some degree of metabolism of the substance will occur in the liver, and that the water-soluble metabolites, e.g. glucuronides and carboxylates, will be eliminated via urine.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
No details on metabolites are available. Based on data from analogous substance BADGE the hydrolysis of the phenyl ether moiety will not occur. It is possible that the substance may be glucuronidated at least to some extent at the terminal hydroxyl moieties, or that one of the diol groups can be oxidized to yield the α-hydroxycarboxylic acid and, after decarboxylation, carboxylic acid.

Applicant's summary and conclusion

Conclusions:
Based on the results of the toxicokinetic assessment, absorption values of 100%, 100% and 50% are derived for oral, respiratory and dermal absorption of the substance, respectively. Upon uptake via gastrointestinal tract the substance is probably distributed to the liver, where it can be partially oxidized to yield the α-hydroxycarboxylic acid and, after decarboxylation, carboxylic acid, or glucuronidated at the terminal hydroxyl groups. High molecular weight constituents are probably undergoing faecal and biliary excretion, while water-soluble metabolites can be excreted in urine. Based on adverse effects in the 28-day study, the substance and/or its water-soluble metabolites can be distributed through the body by systemic circulation. Some degree of accumulation in adipose tissue cannot be excluded for highly apolar constituents.
Executive summary:

Toxicokinetic assessment for the test item was performed based on the analysis of all available information, i.e. structural and physico-chemical properties and the results of available toxicological studies. Based on signs of systemic toxicity in the available 28-day study with developmental/reproductive toxicity screening, the substance is absorbed by oral route. The default 100% oral absorption is assumed for risk assessment purposes. The substance is not volatile (vapour pressure < 1.5 × 10 -3 Pa), and based on the aggregation state of the substance (highly viscous liquid) it is not likely that the substance can reach the nasopharyngeal region or subsequently the tracheo/bronchial/pulmonary region via inhalation of vapour. However, the default value of 100% is assumed for respiratory absorption for risk assessment puprposes. As the major fraction of the substance consists of the substances with high molecular weight (21% with MW > 1000 g/mol, 72% with MW in the range of 392 -952 g/mol) and high log Pow (range from < 0.3-7.2), 50% dermal absorption is considered as a worst-case value. Based on observed effects in the available 28-day toxicity study, upon uptake via gastrointestinal tract the substance is transported to liver where it is probably (partially) metabolized. As the bis-diol structures have been shown to be stable molecules, the hydrolysis of the phenyl ether moiety will not occur. It is possible that the substance may be glucuronidated at least to some extent at the terminal hydroxyl moieties, or that one of the diol groups can be oxidized to yield the α-hydroxycarboxylic acid and, after decarboxylation, carboxylic acid. Based on developmental effects observed in the same study, water-soluble constituents and/or metabolites can be distributed to other organs and tissues by systemic circulation. Based on high molecular weight and high log Pow of some components, some degree of accumulation in adipose tissue cannot be excluded. Biliary and fecal excretion of some constituents may be expected to occur based on the molecular weight and high log Pow of the substance, while water-soluble metabolites, e.g. glucuronides and carboxylates, will be eliminated via urine.