Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Well documented expert statement based on a series of physicochemical and toxicology studies with NA-11 or a formulation of it, in general performed according to technical guidelines and in compliance with GLP in internationally recognized contract research organizations.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Expert statement based on a series of physicochemical and toxicology studies with NA-11 or a formulation of it. Technical guidelines followed in these experimental studies are cited in the respective endpoint study records.
GLP compliance:
no
Remarks:
Considered unnecessary for expert statement

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: NA-11 or formulation of it
Further details on the test material used in the experimental studies referred to are presented in the respective endpoint study records.
Radiolabelling:
no

Test animals

Species:
other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement
Strain:
other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement
Sex:
male/female
Details on test animals and environmental conditions:
Detailed in the endpoint study records of in-vivo studies referred to in the present expert statement.

Administration / exposure

Route of administration:
other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement
Vehicle:
other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement, if appropriate
Details on exposure:
Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.
Duration and frequency of treatment / exposure:
Detailed in endpoint study records referred to in the present expert statement.
Doses / concentrations
Remarks:
Doses / Concentrations:
Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.
No. of animals per sex per dose:
Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.
Control animals:
other: Detailed in endpoint study records referred to in the present expert statement, if applicable
Positive control:
Detailed in endpoint study records referred to in the present expert statement, if applicable
Details on study design:
Detailed in endpoint study records referred to in the present expert statement, if applicable
Details on dosing and sampling:
Detailed in endpoint study records referred to in the present expert statement, if applicable
Statistics:
Detailed in endpoint study records referred to in the present expert statement, if applicable. Not applicable for the present expert statement.

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
NA-11, the sodium salt of an organic molecule, has a molecular weight of 510 Da and the following physical-chemical properties: moderate water solubility of 1.85 g/L (at 20°C), partition coefficient Log Pow = 0.8 at neutral pH. In the non-ionised form at pH 1 Log Pow was determined at a value > 6.2. These properties favour absorption after oral exposure. In the repeat oral dose toxicity study the substance was absorbed since systemic toxicity was observed.
The above given physical-chemical properties of NA-11 could be favourable for dermal uptake [1]. However, based on the molecular weight of 510 Da dermal absorption may already be limited due to the size of the molecules. No dermal effects were observed in skin irritation and skin sensitization tests.
The partition coefficient Log Pow = 0.8 and the moderate water solubility of 1.85 g/L (at 20°C) of NA-11 are favourable for absorption directly across the respiratory tract epithelium by passive diffusion [1]. In view of the very low volatility of NA-11 (vapour pressure of 0.11 Pa at 20°C) exposure to the vapour form will be limited. With regard to the large proportion of inhalable particles (approx. 25% with a diameter < 10 µm) exposure to dust of NA-11 has to be avoided. The read-across source substance for acute inhalation toxicity, NA-70 - differing only in the cation (lithium instead of sodium), was acutely toxic by inhalation in rats.
[1] ECHA 2008, Chapter R.7c: Endpoint specific guidance
Details on distribution in tissues:
There are no data on the distribution of NA-11 in tissues. Based on the effects observed in the oral repeated dose toxicity study with the screening for reproductive and developmental toxicity the substance is distributed in the whole body. In parental animals after 29 days of exposure effects in the liver were observed in the histopathology examinations. In general, animals of the high dose group showed reduced food intake and growth. In contrast to these observations, in a 90 day oral toxicity study in rats (from 1986) no clear signs of toxicity were observed.
Details on excretion:
There is no indication in the available study results regarding the excretion of NA-11 or components thereof.

Metabolite characterisation studies

Metabolites identified:
not specified

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
No specific study was performed on the absorption, distribution, metabolism and/or excretion (ADME) of NA-11.

After oral administration NA-11 is rapidly absorbed and systemically distributed. Systemic availability of NA-11 after dermal application is very liimited based on the molecular size of the substance.

Availability of NA-11 under a vapour state is very limited, because of its low vapour pressure. However, the substance is a fine powder with approx. 25% of particles with a diameter < 10 µm which can be inhaled and become systemically available.

All available study results gave no indication regarding the metabolic pathway, distribution or excretion of NA-11. Bioaccumulation was not specifically investigated, but in view of the low partition coefficient at neutral pH, LogPow = 0.8, NA-11 is not considered to be bioaccumulative .