Dinonylnaphthalenedisulphonic acid

Endpoint summary

Description of key information

A theoretical assessment is included

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

10

Additional information

Toxicokinetics

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]. DNNDSA has a measured water solubility of >2000 mg/L (>98%) and therefore the substance is expected to dissolve into the gastrointestinal fluids. Uptake by passive diffusion is expected to be limited in view of the low logPow and the size of the molecule. The structure contains ionizable groups (SO3H) and is expected to be present in ionized form, which might hamper diffusion across biological membranes. The uptake of the source chemical is also hampered by its size and logPow. This compound is, however, very hydrophobic, which will limit uptake, although this characteristic will enable micellular solubilisation by bile salts in the gastro-intestinal tract which allows crossing of lipid biomembranes.

The acidic nature of both substances is expected to cause local effects. This is confirmed by the outcome of the repeated dose toxicity test on DNNSA, where local effects were seen in the gastro-intestinal tract (hyperkeratosis of the forestomach epithelium, mucosal hyperplasia and increased severity of lymphogranulocytic inflammation in the caecum and increased amounts of mucus in the large intestines). At 893 mg/kg 4 of 10 males and 1 of 10 females were killed in extremis. These animals as well as survivors at 298 and 893 mg/kg had decreased food intake and lower body weight (gain). Next to the local effects, lymphoid atrophy of the thymus, decreased severity of haemopoietic foci in the spleen, increased severity of alveolar foamy macrophages in the lungs and scattered hepatocellular vacuolation in the liver were observed at the high dose level. Based on these data it is concluded that the source substance, DNNSA, interferes with the integrity of the epithelium lining the GI tract, which will enhance absorption and the systemic effects can be considered secondary to the local effects. The NOAEL in the study was 95 mg/kg bw.

As the target substance, DNNDSA, is even more acidic than the source chemical, similar effects on the gastro-intestinal tract lining can be expected. Although the physico-chemical properties determining uptake are very different, the overall effect will be that uptake of DNNDSA is expected to be similar to that of DNNSA with the primary effect being on the gastro-intestinal tract lining. The damage of this lining may lead to a higher absorption of both substances than would have been expected on their physicochemical properties.

For risk assessment purposes, absorption of DNNDSA by the oral route is set at 100%, based on the expected effects on the gastro-intestinal tract due to its acidic nature

 

The metabolism of DNNSA and DNNDSA 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 either substance, 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 DNNDSA, which is a disulphonic acid with much longer alkyl chains than 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 test substance throughout the body is not expected based on its molecular size (ca 19.70 Å). In general, molecules of this size do not pass readily through cell membranes, thus limiting wide distribution. Based on its size and its water solubility, distribution is expected to be limited.

 

The low vapor pressure (estimated <1E-19 Pa at 20°C) indicates that DNNDSA 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 DNNDSA 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 DNNDSA is set at 10%.

 

When DNNDSA comes in contact with the skin, the first layer of the skin, the stratum corneum, forms a barrier for hydrophilic compounds. The logPow of 0.3 suggests that the substance will not be taken up in the stratum corneum. The structure contains ionizable groups (-SO3H) that are expected to hamper penetration of the substance, because ionized substances do not readily diffuse across biological membranes. An acute dermal toxicity study showed that DNNDSA is not toxic via skin application (the highest dose 1100 mg/kg bw as act ingr. did not cause mortality), which is provides indications for of low absorption. The skin irritation study with a formulation did not find any irritation, but it would have been expected that the acidic nature (pH 1-2) of the substance when administered as such would have caused severe damage. In general salts of the source substance DNNSA 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 DNNDSA is corrosive, but has a large molecular weight that would limit uptake. Therefore it is difficult to draw a conclusion on dermal absorption. In a worst case it is assumed to be 100%.