Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: toxicokinetic assessment based on avaialble data
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Prelimary assessment based on physical-chemical and toxicological data according to REACH guidance in information requirements R 7c, 2008.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
according to
Guideline:
other: ECHA guidance on information requirements R 7c, 7.12, 2008
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
3.1.1. Oral
Based on the physical chemical properties, a molecular weight below 500, a slight water solubility and a log Kow of 2.1, it is anticipated that the substance is readily absorbed via the oral route. This is supported by the acute and subacute toxicity observed after oral administration to rats. The slight surface activity can increase the oral absorption. pKa modeling indicated that in the physiological pH-range between pH 2 in the stomach and pH 8.6 in the intestine, the substance is likely protonated on both nitrogen atoms. While the charge could lower the diffusion through mucous membranes, it can also lead to an increase in surface activity and formation of micelles that can be readily absorbed.
3.1.2. Dermal
At the skin pH of 5 to 6 the substance is likely protonated at both nitrogen atoms. Dermal absorption is anticipated to be lower than the oral absorption as the substance will have less water available to dissolve and form micelles. However, the log Kow of 2.1 indicates the possibility of dermal absorption. The substance is also irritant to skin, which could enhance skin absorption. The skin sensitizing properties indicate a potential for dermal absorption as well. As the substance has a low vapour pressure, its absorption will not be considerably lowered by evaporation on the skin.
3.1.3. Inhalation
Due to the low vapour of the substance inhalation exposure to vapours is unlikely. In the case of aerosol formation ready absorption in the respirable tract can be anticipated from the physical chemical properties. Due to the protonation and surface activity under physiological conditions, it is however likely that the substance dissolves readily in the mucous and it is anticipated that a considerable proportion is swallowed in the mucous and will not reach the lung.
Details on distribution in tissues:
The log Kow of 2.1 indicates that the substance can distribute into cells. The ionization at physiological pH makes it likely that the substance mainly distributes in the aqueous compartments and both the log Kow and the protonation indicate that the substance is unlikely to distribute into lipid compartments. The toxicological target organs after oral administration indicate that the substance or metabolites are distributed to the liver and the lung and excreted via the kidney.
Details on excretion:
3.4. Excretion
Due to the protonation of the substance and the likely formation of a number of hydrophilic and smaller metabolites, and excretion via the kidneys and the urine is likely. This is also corroborated by histopathological findings in the kidneys in the repeated dose study. It is possible that some smaller metabolites are exhaled via the lungs as some findings in the lungs were also reported in the repeated dose study.

Metabolite characterisation studies

Details on metabolites:
3.3. Metabolism
From the structure of the substance, several oxidative metabolic pathways that take place in the liver can be anticipated. As secondary aliphatic amine, N-oxide formation is possible, but is likely to be sterically hindered by the bulky side chains. Side chain hydroxylation is more likely and can occur at the methyl-goups of the dimethyl-butyl side chain or in the hexane chain (likely in beta-position to the N-atom). Methyl-hydroxylation can be followed by further oxidation resulting in dimethylation. Hydroxylation in the n-hexane chain could be followed by further oxidation to the keto-group. N-dealkylation is also a possible metabolic pathway. Further, hydroxides can also be conjugated in phase II reactions to glucuronides or sulfates. All likely metabolic pathways lead to more hydrophilic compounds that are anticipated to be readily excreted by the kidneys via the urine. The finding of liver hypertrophy in the repeated dose study provides an indication of liver metabolism and liver enzyme induction taking place.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the physical chemical data and the results of the toxicological studies, the substance is readily absorbed via the oral, dermal and inhalation route. Dermal absorption is likely smaller than oral absorption and if inhalaed the substance is likely to be dissolved in the mucus and swallowed. It is unlikely that it reaches the lower respirable tract via inhalation exposure. The substance is likely distributed in the aqeous compartments. Metabolism in the liver is likely and several hydrophilic and smaller metabolites can be predicted. Excretion is expected mainly via the urine due to the ionised charcter of the substance and polar metabolites. An exhalation of smaller metabolites via the lung is also possible.
Executive summary:

Based on the physical chemical data and the results of the toxicological studies, the substance is readily absorbed via the oral, dermal and inhalation route. Dermal absorption is likely smaller than oral absorption and if inhalaed the substance is likely to be dissolved in the mucus and swallowed. It is unlikely that it reaches the lower respirable tract via inhalation exposure. The substance is likely distributed in the aqeous compartments. Metabolism in the liver is likely and several hydrophilic and smaller metabolites can be predicted. Excretion is expected mainly via the urine due to the ionised charcter of the substance and polar metabolites. An exhalation of smaller metabolites via the lung is also possible.