Reaction product of naphthalene, propan-2-ol, sulfonated and neutralized by caustic soda

Endpoint summary

Description of key information

The available experimental data in animals support limited absorption and systemic distribution of the test substance and/or its metabolites or degradation products through the inhalation, oral and dermal route. The limited systemic absorption and distribution was evidenced by macroscopic or organ weight changes in the liver (inhalation), adrenals (oral), and blood vessels of the stomach and small intestine (dermal). The registered substance seems to be metabolized in bacteria as demonstrated by higher cytotoxicity in the presence of metabolic activation in the Ames test. However, in the absence of specific metabolism studies, no conclusion on the relevance of this variation to human can be drawn. No specific indication on the test substance excretion was obtained from the toxicity studies.

Additional information

No specific toxicokinetic studies are available on Reaction product of naphthalene, propan-2-ol, sulfonated and neutralized by caustic soda. A toxicokinetic assessment was made, based on the physico-chemical properties of the test substance and the results of toxicity studies (acute oral, inhalation and dermal toxicity, skin sensitisation,in vitro genotoxicity studies and repeat dose toxicity studies).

 

Physico-chemical properties :

Molecular weight: between 273 and 357 g/mol (UVCB)

Water solubility: 604 g/L (at 20°C)

Partition coefficient in octanol/water: -0.27 (at 20°C)

Particle size: D(0.1) = 10.858 μm ;D(0.5) = 34.304 μm; D(0.9) = 71.764 μm.

Vapour pressure: 2.1 x 10-5 Pa (at 25°C)

Boiling point: >500 °C

Density: 1.525 (at 20°C)

 

Absorption and distribution :

Inhalation:

In the acute inhalation toxicity study, mortality was observed in rats exposed for 4 hours to aerosol of Reaction product of naphthalene, propan-2-ol, sulfonated and neutralized by caustic soda. Indeed premature death was recorded in 2/10, 6/10 and 8/9 rats at target dose levels of 1, 2.5 and 5 mg/L, respectively. Clinical signs such as labored, noisy and/or gasping respiration, sneezing, increase of respiratory rate, decrease of activity and/or hunched posture were observed at all concentrations. Necropsy revealed a dark/red discoloration of the non-collapsed lungs and the presence of white foamy material in the trachea in animals treated at all concentrations except the lowest (0.5 mg/L). These findings were associated with enlargement and red discoloration of the liver and presence of clear/beige liquid at the fur of head or of the perinasal area in most high dose animals. Whereas the clinical signs and macroscopic findings in the lungs and trachea are indicative of a local irritating effect, the changes in the liver are consistent with an absorption and systemic distribution of the registered substance and/or its metabolites or degradation products by the inhalation route. The capacity of the substance to be absorbed through the respiratory tract is supported by the significant proportion of respirable particles (<15 µm). In the sub-acute and sub-chronic toxicity studies, only adverse effects in the lungs indicative of a local irritation were reported and there were not relevant systemic toxicity apart from a slight effects on body weight from the dose of 0.01 mg/L.

Oral:

In the acute oral toxicity study, mortality was observed in rats exposed to one single oral (gavage) administration of Reaction product of naphthalene, propan-2-ol, sulfonated and neutralized by caustic soda dissolved in water at the dose of 1800 mg/kg bw. Clinical signs such as piloerection, decreased motor activity, hypertension and loss of grip were noted in animals treated with 1800 mg/kg bw. Apart from the clinical signs, there was no obvious evidence of systemic toxicity. In the OECD 422 rat study, clinical signs consisted in emaciated appearance observed from 100 mg/kg/day in a few males and hypoactivity and loud/abdominal breathing observed at 300 mg/kg/day in some females. A decrease in body weight and food consumption was reported in males given 300 mg/kg/day. Minimal increases in adrenal weights were seen in females given the test item at 300 mg/kg/day. Although of equivocal significance due to the absence of microscopic correlates, this variation supports a limited absorption and systemic distribution of the registered substance and/or its metabolites or degradation products by the oral route.

Dermal route:

In the acute dermal toxicity study performed in rabbits, Reaction product of naphthalene, propan-2-ol, sulfonated and neutralized by caustic soda applied on the skin as an aqueous paste induced mortality in animals treated with 5000 and 10000 mg/kg bw. Signs of skin irritation were observed at these doses. The congestion of the blood vessels of the stomach and small intestine also seen at necropsy is indicative of a limited absorption and systemic distribution of the registered substance. Furthermore, the in vivo skin sensitization test (LLNA) confirmed this absorption capacity as increase of the stimulation index was observed in treated mice (topical exposure of the ear). Despite the fact that obtained results were considered as equivocal regarding the sensitization potential, they showed that the registered substance is able to pass the dermal barrier to encounter the systemic circulation and induce the proliferation of lymphocytes in the lymph node draining the site of application. This capacity to penetrate the skin is supported by the high solubility of the substance.

In both experiments (Acute dermal toxicity and LLNA), the registered substance was tested as an aqueous paste or diluted in propylene glycol, respectively. The used vehicle has probably enhanced the dermal absorption of the registered substance. As the registered substance is a powder, it can be assumed that its dermal absorption is relatively limited.

 

Metabolism:

Four in vitro studies assessed the potential genotoxicity of Reaction product of naphthalene, propan-2-ol, sulfonated and neutralized by caustic soda. Two Ames tests (CitoxLab 2012 and Marzin 1980), a chromosome aberration test in cultured human lymphocytes (CitoxLab 2012) and a mouse lymphoma assay (CitoxLab 2012); all gave negative results. In the second experiment of the Ames test performed in 2012, moderate to strong cytotoxicity was observed in all tested strains at the highest concentration only (5000 µg/plate) in the presence of metabolic activation (pre-incubation method). No cytotoxicity was observed without metabolic activation. Therefore the toxicity reported in the presence of S9 mix suggests that the registered substance is metabolized and the synthesized metabolite(s) is(are) toxic to bacterial strain at this dose level. However, in the absence of specific metabolism studies, the relevance of this variation to human is unclear. In the Mammalian mouse lymphoma assay and chromosome aberration test, cytotoxicity was observed both in the presence and absence of metabolic activation, at similar dose levels. Therefore no conclusion on the metabolism can be drawn from these two tests.

Elimination

There is no indication of a preferred route of excretion for Reaction product of naphthalene, propan-2-ol, sulfonated and neutralized by caustic soda but its high water indicate that excretion of unchanged parent substance and/or metabolites could occur by renal or biliary routes and that bioaccumulation is unlikely.