Methanesulfonic acid, 1,1'-(1,6-hexanediyldiimino)bis[1-oxo-, sodium salt (1:2)

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Statement on toxicokinetics of [1,1’-(1,6-Hexanediyldiimino)bis[1-oxo-methanesulfonic acid] sodium salt (1:2)].

There are no experimental data for substance available and this toxicokinetic statement is based on available data as physico-chemical data, data like skin irritation/corrosion, eye irritation, skin sensitization, in vitro mutagenicity and acute and repeated dose oral toxicity studies. This assumption follows the procedure indicated in the “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance” dated May 2008.

Available physico-chemical information taken into account:

Physical state:

The substance is an organic solid.

Particle size distribution:

The MMAD (Mass Median Aerodynamic Diameter) 48.83 μm as spherical particles.

Structure:

The substance is a salt with ionisalbe groups within the structure.

Molecular weight:

The substance is of the empirical formula: C8H14N4O8S22- x 2 Na+ with a molecular mass of 376. The cation has a molecular mass of 330.

Water solubility:

424 g/l at 22°C and pH 4.

Log P:

The partition coefficient (log Pow) of PCMS was determined to be -3.05 at 25°C at pH 5.

Surface tension:

The surface tension of the aqueous solution of the test substance as test item is 28.1 mN/m at 20 °C.

Vapor pressure:

QSAR determination of the vapor pressure of the substance: 8.76 E-17 Pa at 25°C (related to the acid form).

Estimation of oral absorption:

Oral absorption might be considered, based on the physico-chemical data; a molecular weight below 500 (cation of the substance 330), high water solubility (424 g/l) combined with a molecular mass above 200. On the other hand the low partition coefficient (-3.05) might indicate limited passive diffusion through the GI tract.

Oral toxicity data indicate oral absorption. The substance was investigated in an oral subchronic toxicity study. The compound was administered daily by oral gavage in bid-stilled water as the vehicle at target dose levels of 100, 300 and 1000 mg/kg body weight/day for a period of 90 days. Based on the results of this study, a no-observed effect level (NOEL) could not be established because centrilobular to diffuse hepatocellular hypertrophy was recorded at minimal to slight severity in males treated with 100, 300 and 1000 mg/kg/day. The no-observed-adverse-effect-level (NOAEL) was considered to be 300 mg/kg body. Absorption in the oral toxicity studies is assumed to be high, since bid-stilled water was used as a vehicle and non-adverse diffuse hepatocellular hypertrophy was observed even at the lowest dose tested, 100 mg/kg/day.

Overall, oral absorption is assumed based on the physico-chemical data and the oral toxicity data in a sub-chronic toxicity study. Based on these data the default oral absorption value of 50% is taken in the course of the DNEL calculation.

Estimation of dermal absorption:

Dermal absorption is likely to be low because PCMS is a solid with a molecular mass above 100 (cation of the substance 330), high water solubility above 10 g/l (424 g/l) and a logP value <–1 ((-3.05) which suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum. In addition PCMS is not a surfactant with a surface tension below 10 mN/m which will enhance the potential dermal uptake (substance suface tention: 28.1 mN/m).

Dermal toxicity data also does not indicate relevant dermal absorption:

Skin irritation:

Not irritating

Skin sensitization:

Negative in LLNA

Dermal toxicity data:

In acute dermal toxicity study no intercurrent deaths occurred during the course of the study. No clinical signs were recorded throughout the entire observation period and no macroscopic findings were found at necropsy.

Overall, dermal absorption is assumed to be low. Based on the “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance” an absorption of 10% was chosen for the DNEL calculation, “because there is evidence in the literature that substances with molecular weight and/or log P values at these extremes can to a limited extent cross the skin.” (Footnote page 156).

Estimation of absorption via inhalation:

The substance has a very low vapor pressure (QSAR determination related to the acid form: 8.76 E-17 Pa at 25°C). In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled (substance MMAD 48.83 μm).

Acute inhalation toxicity study:

All animals survived exposure to the test atmosphere. Following exposure all rats exhibited facial staining, nasal discharge and/or abnormal respiration. All animals recovered from the above symptoms by Day 2 and, apart from ocular discharge observed in one male on Days 8 and 9, appeared active and healthy for the remainder of the observation period. Although three males and two females lost or failed to gain body weight by Day 1, they showed a continued weight gain thereafter and along with all other animals gained weight through Day 14. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Overall, the default absorption factor of 100% is assumed for DNEL. This value can be considered conservative based on the physico-chemical data.

Estimation of distribution:

Based on the low LogP (-3.05) and the high water solubility (424 g/l) it is not likely that the substance distributes into cells. This assumption is supported by the oral sub-chronic toxicity study in which only observations in the liver (non-adverse diffuse hepatocellular hypertrophy) were reported at the lowest dose tested, 100 mg/kg/day.

Estimation of accumulation:

Based on the low LogP (-3.05) and the high water solubility (424 g/l) it is not likely that PCMS has an accumulative potential.

Estimation of metabolism:

Based on the low LogP (-3.05) and the high water solubility (424 g/l) it is not likely that the substance is a substrate for phase 1 or phase 2 metabolism. In vitro and in vivo genotoxicity data do not indicate any genotoxic metabolites. The substance is negative in vitro tests in the absence and in the presence of S9 extracts (Ames test, an in-vitro Chromosome Aberration test and a HPRT test) and in vivo in a Mammalian Erythrocyte Micronucleus Test.

Estimation of excretion:

The substance is likely excreted in urine because of its characteristics favorable for urinary excretion: low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine.