Naphthalenesulfonic acid, di-C9-rich C8-10-branched alkyl derivs., calcium salts

Endpoint summary

Description of key information

A substance can enter the body via the lungs, the gastrointestinal tract, and the skin. To determine the absorption rate, the different routes need to be assessed individually.

 

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration [2]. Calcium bis( di C8-C10, branched, C9 rich, alkylnaphthalene sulphonate) has a measured water solubility of 0.266 mg/L and therefore it is expected to dissolve into the gastrointestinal fluids to a very limited extent. Uptake by passive diffusion is possible, but limited due to the high molecular weight of the salt (average MW 959) and its dissociation product DNNSA (MW 461). CaDNNSA has a high log Pow > 6.6), which makes the compound relatively hydrophobic. This characteristic will enable micellular solubilisation by bile salts in the gastro-intestinal tract which allows some crossing of lipid biomembranes. The structure contains an ionizable group (SO3H), which might hamper diffusion across biological membranes. In addition, the molecular size of the molecule of > 19 Å does not favor uptake across the biological membranes.

In the 90-day study on CaDNNSA in the highest dose group 6/10 females died showing alterations in the gastro-intestinal tract, a small thymus and bone marrow atrophy. The surviving females at 1000 mg/kg bw showed similar effects and a reduced body weight (gain). The effects on the gastro-intestinal tract also became apparent in males at 300 and 1000 mg/kg bw. These animals also had a reduced body weight (gain). Other effects included changes in numbers of white blood cells, lymphocytes, platelets as well as effects on several biochemical parameters. Macroscopy and histopathology indicated that next to the GI-tract mainly the thymus and bone marrow could be considered as potentially affected in males at 300 mg/kg bw and above and in females at 1000 mg/kg bw. The effects on blood and blood forming organs as well as on the immune system are indicative for some absorption of the substance. This absorption may be enhanced due to the effects on the gastro intestinal tract lining.

Similar findings were reported in the repeated dose-reproduction study with the analogue DNNSA. In the OECD 422 study on the analogue BaDNNSA systemic effects on the kidney were seen that can be related to uptake of this substance

For risk assessment purposes, the logPow, water solubility, the high molecular weight and the molecular size of CaDNNSA do not favor absorption via the oral exposure route. However the effects on the gastro-intestinal tract are likely to increase systemic exposure. Therefore, absorption of CaDNNSA by the oral route is set at 100%, based on the evidence of systemic toxicity as seen in studies on the substance itself as well as its analogues.

 

The metabolism of DNNSA salts is mainly contingent on both the nature of the alkyl groups and the nature and extent of naphthalene ring substitutions. There are currently no metabolism studies of CaDNNSA, however, the US EPA has evaluated the metabolism of analogs in in the sodium alkyl naphthalenesulfonate cluster (SANS), a group of sodium salts of naphthalenesulfonic acids [3]. In a US EPA final rule for SANS, it was stated that “the 1- or 2-sulfonic acid sodium salt moieties on the naphthalene ring may provide a handle by which these compounds can be readily conjugated and eliminated.”  Though the available information is not definitive for CaDNNSA, where the alkyl chains are much larger than for the naphthalenesulfonic acids evaluated by EPA, it is expected that the metabolism of the substance will be a factor, enhancing elimination.

 

If absorbed, wide distribution of the CaDNNSA throughout the body is not expected based on its molecular size (> 18 Å). In general, molecules of this size do not pass readily through cell membranes, thus limiting wide distribution. Excretion of CaDNNSA and its potential metabolites will occur via the bile (high molecular weight) or the urine (low molecular weight).

 

The low vapor pressure (estimated <6.4E-12 Pa) indicates that CaDNNSA has a very low volatility and is not expected to evaporate and be available via inhalation. Moreover, aerosols with inhalable or respirable droplets which would reach the respiratory tract are not expected from the current uses of this substance. If CaDNNSA reaches the tracheobronchial region, the uptake via biological membranes would be limited based on its molecular size.

Based on the above data, for risk assessment purposes the inhalation absorption of CaDNNSA is set at 10%.

 

When CaDNNSA comes in contact with the skin, the first layer of the skin, the stratum corneum, forms a barrier for hydrophilic compounds. The logPow of >6.6 suggests that the substance can be taken up in the stratum corneum. However, the water solubility (0.266 mg/l) will limit the transfer between the stratum corneum and the epidermis to a certain extent.

The structure contains an ionisable group (-SO3H) that is expected to hamper penetration of the substance, because ionized substances do not readily diffuse across biological membranes. An acute dermal toxicity study showed that CaDNNSA is not toxic via skin application, which is also indicative of low absorption. In general DNNSA salts are irritating to the skin, but not corrosive, a characteristic that might enhance dermal absorption.  

According to the criteria given in the REACH Guidance [1], 10% dermal absorption will be considered in cases where the MW >500 and log Pow <-1 or >4. Weight of evidence indicates that CaDNNSA can be assumed to have a dermal absorption of 10%: 1) the molecular weight (957) greatly exceeds the criterion 2) the log Pow is considerably outside the stated range >6.6) and 3) skin irritation testing did not report any corrosive effects which would enhance absorption.

In conclusion, the dermal absorption for risk assessment purposes of Calcium DNNSA is set at 10%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10