Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Toxicokinetics assessment
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
There are no experimental data. A preliminary assessment was made based on the information currently available from the dataset. The information doesn't come from a toxicokinetics study so the minimum fields required cannot be filled in. See Toxicokinetics Assessment under executive summary section.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: low bioaccumulation predicted based on available information from other studies in the current dataset
Based on the data currently available from the dataset, the substance is considered to present a low systemic bioavailability. This is further supported by the low toxicity profile observed.
Executive summary:

Toxicokinetics Assessment

There are no experimental data. A preliminary assessment was made based on the information currently available from the dataset.

 

ABSORPTION

No substance-specific absorption data were available experimentally by any route.

 

1) Skin absorption

Skin permeability estimates:

Input parameters:

MW = 537

log Kow = -1.98

Based on the log Kow a poor lipophilicity is predicted. The MW above 500 is also not in favour of dermal absorption.

 

As estimate of the permeability coefficient (maximum flux across the skin) was conducted using various mathematical models:

 

> Potts & Guy :           logKp = 0.71logKow – 0.0061MW – 2.72

logKow = -7.405          

Kp = 3.96 10-8 cm/h

sources :

- Potts & Guy (1992).Pharm.Res. 9:6693-669

- www.cdc.gov/niosh/topics/skin/skinpermcalc.html

 

> Frasch

logKow = -9.3              

Kp = 4.96 10-10  cm/h

source : www.cdc.gov/niosh/topics/skin/skinpermcalc.html

 

> Modified Robinson   

logKow =-5.17            

Kp = 6.77 10-6    cm/h

source :www.cdc.gov/niosh/topics/skin/skinpermcalc.html

 

> SkinPerm                                         

Kp = 8.83 10-7cm/h

source :http://home.planet.nl/~wtberge/qsarperm.html

 

 

The various mathematical models based on hydrophobicity properties and molecular weight provided Kp estimates ranging from 8.83 10-7(SkinPerm) to 4.96 10-10(Frasch). These figures are all below 10-6 and support a very low percutaneous absorption capacity (Howes et al., 1996. Methods for assessing percutaneous absorption. The report and recommendations of ECVAM Workshop 13. ATLA 24:81-106).

 

Other considerations:

The molecular weight of 537 Dalton, and the presence of cationic charged functions are not in favour of a passive diffusion accross biological membranes. (H. Schaefer, T. E. Redelmeier (eds). 1996. In: Skin Barrier – Principles of percutaneous absorption.S. Krager AG (publ.))

Furthermore, the acute dermal toxicity study at level up to 4840 mg/kg (dose expressed for the registered substance, with the residual water necessary to ensure stability), i.e. 2000 mg/kg of the main constituent, did not show any signs of systemic toxicity. No clinical signs were noted during the 15-day observation period.

No damages or alteration of the skin integrity are expected as the substance did not induce any signs of skin irritation in vivo.

 

 

2) Oral absorption

The molecular weight of 537 Dalton, high hydrophilicity and logP value below -1.98 are not in favour of absorption by passive diffusion from the gastro-intestinal tract.

The hydrolysis study conducted under 3 different pH conditions showed that the substance was stable. The results of the tests at pH 4.0, pH 7.0 and pH 9.0 showed no significant degradation of TRIQUAT Monomer at 50 °C. The degradation of TRIQUAT Monomer was less than 10% after 5 days.

 

No signs of systemic toxicity were observed in the acute oral toxicity study in rats with a dose of 4760 mg/kg of the registered substance (dose expressed for the substance as registered, with the residual water content necessary for the stability, i.e. equivalent to 2000 mg/kg of the main constituent).

Limited systemic toxicity was also noted in the repeated oral dose toxicity study at a maximum dose of 2420 mg/kg/day of the registered substance, i.e. 1000 mg/kg/day of the main TRIQUAT constituent.

The low toxicity and absence of target organs is consistent with a limited absorption of the TRIQUAT constituent by the oral route

 

3) Absorption by the inhalation route

There are no experimental data related to the potential absorption by the inhalation route.

The substance is manufactured in water and the registered substance consists in up to 50% residual water necessary to ensure the stability.

Physico-chemical properties support a moderate volatility potential. The Vapour Pressure could not be determined experimenlaly because of the presence of residual water necessary to maintain the stability of the substance. It was estimated by calculation based on the constituents and their molar fraction (see section 4.6). The model estimate for the Vapour pressure of the Triquat constituent was found to be negligible [8.86E-09 Pa, or 2.93E-10 Pa for the partial pressure of the constituent in solution] as compared to that of the water. The estimated Vapour Pressure of 3062 Pa is thus close to that of water.

The molecular weight, logKow, cationic nature, and high hydrophilicity are not in favour of absorption through the respiratory epithelium.

Furthermore, there is no expected exposure to inhalable aerosols during the process and use.

 

 

 

DISTRIBUTION

There are currently no data available that can allow assessment of the potential distribution of the substance in the body.

Based on the logKow estimate (-1.98) the substance has a low lipophilicity and hence a low potential for bioaccumulation (a high water solubility and a very low solubility in n-octanol were reported elsewhere in this dataset).

There was no specific target organ identified in the 28-day repeat dose toxicity study nor in the reproduction/development screening study by the oral route that could indicate a distribution pattern.

 

 

 

METABOLISM

There are currently no data available to appropriately assess the metabolisation of the registered substance.

There are no data available regarding potential enzymatic hydrolysis following ingestion. However the oral ingestion is not the most likely exposure route for the worker in an industrial setting.

There are no data on potential metabolisation on contact with skin or by the inhalation route.

 

 

EXCRETION

There are currently no data on potential excretion of the registered substance.

There was no observation available from the repeated dose toxicity studies providing information on potential absorption, metabolisation and excretion of the substance or metabolites.

 

 

Based on the data currently available in the dataset, both from the physico-chenical properties and toxicological data, the substance is considered to present a low systemic bioavailability. This is further supported by the low toxicity profile observed.