DESCRIPTION FIELD OF THE INVENTION

The present invention relates to a composition comprising resveratrol, L-tryptophan, L- aspartic acid and vit. B3 able to control the biosynthesis of nicotinamide adenine dinucleotide (NAD ⁺ ) for the purpose of producing a greater amount of substrates for reactions catalysed by Sirtuinl (SIRT1) and increasing the action of resveratrol. Within the scope of the present invention, among the various isoforms of vitamin B3 reference will be made solely to β-nicotinamide adenine dinucleotide hydrate. The invention also relates to the use of such a composition in the pharmaceutical, nutritional and cosmetic fields.

2) STATE OF THE ART

It is known that resveratrol (3,5,4'-trihydroxystilbene) is a polyphenol present in grape and in numerous plants (Fremont, 2000). Numerous studies have shown how regular consumption of red wine may be able to reduce the incidence of atherosclerosis and cardiovascular diseases in spite of a diet rich in saturated fats (French paradox) (Renaud and de Lorgeril, 1992). This beneficial effect has been attributed just to the presence of resveratrol in red wine, defined as one of the most powerful antioxidants present in nature. Numerous studies have shown how resveratrol may be able to protect the heart (Daset al.,1999), brain (Della-Morte et al, 2009) and kidneys (Giovannini et al.,2001) against damage caused by ischemia/reperfusion. The protective effects are based on the ability of resveratrol to reduce lipid peroxidation, to promote vasodilation, reduce serum levels of cholesterol and triglycerides, and to reduce platelet aggregation and consequently control all mechanisms associated with the development of atheroma plaques (Fuhrman et al.,1995; Hao and He, 2004; Zern et al., 2003). In addition to its beneficial effects with regard to cerebral and cardiovascular diseases, resveratrol has also been shown to exhibit a protective effect in the case of Parkinson's disease, cerebral oedema, Alzheimer's disease and lateral amyotrophic sclerosis (Savaskan et al., 2003; Zhuang et al.,2003; Raval et al.,2008). Recently, in vitro and in vivo studies have demonstrated how resveratrol is able to extend the average life expectancy in all tested animals (Yang et al., 2007; Baur et al., 2006). Thanks to considerable research, we now know that resveratrol is able to mimic the antioxidant metabolic effects of calorie restriction and thus slow down the ageing process (Sinclair et al., 2006; Baur et al.,2006). Recent studies have shown how pre- treatment with low doses of resveratrol may be able to protect laboratory animals against cerebral ischemia by mimicking the protective effects of ischemic preconditioning (IPC) (Delia Morte et al., 2009). Ischemic preconditioning (IPC) is an endogenous protection mechanism via which short, repeated ischemic episodes are able to protect the organ against a more prolonged ischemic episode (Abete et al., 2009). This protection mechanism is lost with age (Abete et al. 2009; Delia Morte et al., 2008) and is protected only by the effect of calorie restriction and by increased physical activity (Abete et al., 2000, Abete et al., 2006). Resveratrol, therefore, is a candidate compound in treatment aimed at restoring the protective effects of IPC in senior subjects.

The latest research has demonstrated how the anti-ageing effects and the protective effects with regard to cardiovascular diseases are caused by the ability of resveratrol to increase the activity of SIRT1 (Delia Morte et al., 2009; Raval et al., 2006). In our experiments, low doses of resveratrol (10 mg/kg of body weight), injected into rats intraperitoneally, significantly increased the activity of SIRT1 in hippocampus neurons compared to control rats. It is also significant that ischemic preconditioning (IPC) increased the activity of SIRT1.

SIRT1 is a member of the family of the 7 sirtuins. Just like the other 6, it is orthologue of Sir2 (silent information regulator 2) and possesses NAD ⁺ -dependent deacetylase activity (Blander and Guarente, 2004; North et al., 2003). In cells, SIRT1 is localised in the nucleus. It is certainly the most studied among the family of sirtuins. It is transcribed ubiquitously in numerous human tissues and its activation is controlled by calorie restriction (Cohen et al., 2004). Via the mechanism of deacteylation, it controls numerous transcription factors such as P53, FOXO, ku70, TAFI168, myoD, p3000 and PGC1a (Haigis and Sinclair, 2010; Brunete et al., 2004) and thus controls numerous vital processes including cell cycle, metabolism of fatty acids, axonal neurodegeneration, differentiation between muscular cells, and the processes at the root of ageing (Kim et al., 2007; Potente et al., 2007). Thanks to its many effects, SIRT1 is also implicated in the control of the progression of cardiovascular diseases. In fact, if activated it is able to reduce lipid profile, increase the release of insulin from pancreatic beta cells, reduce inflammation, reduce the development of atherosclerosis and reduce the ageing process, which is the primary risk factor of cardiovascular diseases (Bordone et al., 2006; Rutanen eta al.; Tang, 2006; Yamamoto et al., 2007; Zhuang et al., 2003). The possible cutaneous application of SIRT1 activators is also significant. Both resveratrol and the direct activation of SIRT1 turned out to be protective with regard to skin damage caused by the production of free radicals (ROS) and UVB rays, thus preventing skin ageing (Cao et al., 2009).

In addition to antioxidant activity, the cosmetic efficacy of products activating SIRT1 is mainly based on the ability to repair nuclear DNA, having a significant effect against the signs of senescence (Moreau et al., 2007).

The object of the present invention is to provide a composition which can boost the effect of resveratrol through the production of a greater amount of substrates for reactions catalysed by SIRT1 , and also the use of said composition in the pharmaceutical, nutritional and cosmetic fields.

The present invention relates to the composition of claim 1 and the following claims. Brief description of the drawings

The present description is accompanied by three sheets of drawings, in which:

Fig. 1 , Fig. 2 and Fig. 3 show the results of tests comparing the effects of the composition according to the invention and of compositions belonging to the prior art. Tryptophan is an amino acid which is essential to the human organism, that is responsible for the increase in plasma serotonin and melatonin levels and consequently promotes an improvement in mood and in the sleep-wake cycle. It is the amino acid necessary in the biosynthetic pathway of NAD ^* .

L-aspartic acid is a non-essential amino acid involved in the synthesis of adenosine triphosphate (ATP) and of arginine which promotes an improvement in the response of the organism to stress and fatigue. Similarly to tryptophan, it is involved in the direct synthesis of NAD ⁺ .

Vitamin B3 reduces the plasma levels of cholesterol and triglycerides in the organism and is known to contain more biologically active isoforms. Within the scope of the present invention, reference will be made solely to β-nicotinamide adenine dinucleotide hydrate. To this end, it is noted that the majority of studies concerning resveratrol and SIRT1 activation have used vitamin B3, in particular nicotinamide, as the isoform β- nicotinamide adenine dinucleotide hydrate, as an inhibitor of SIRT1 activation and, consequently, as an inhibitor of the beneficial effects of resveratrol. Reference is made to a number of exemplary passages "The family of dependent deacetylase NAD ^* proteins, Sir2 (or sirtuins) Out of all the NAD ^* -similar and intermediate metabolites of the recovery pathways analysed with regard to ability to exert regulating activity on Sir2 enzymes, only nicotinamide demonstrated a level of inhibition consistent with a physiological role. Nicotinamide is still the most powerful inhibitor of Sir2 enzymes" (Borra MT et al., Mechanism of Human SIRT1 Activation by Resveratrol. J Biol Chem. 2005 Apr 29;280(17):17187-95) (Kaeberlein M, et al,. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29;280(17): 17038-45). (Kaeberlein M, et al,. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29;280(17): 17038-45). Consequently, the use of β-nicotinamide adenine dinucleotide hydrate in combination with other components necessary for increasing SIRT1 activation is completely innovative.

There are various preparations containing resveratrol either alone or in combination with other natural polyphenols and antioxidants (for example selenium, vitamin E), however, according to recent studies their ability to increase SIRT1 activation is very limited. The beneficial abilities of these compounds are based substantially on the supposed synergistic action of the various components through the activation of more cellular pathways, which should provide a unique favourable result.

Summary of the invention

The present invention relates to a composition comprising resveratrol, L-tryptophan, L- aspartic acid and β-nicotinamide adenine dinucleotide hydrate for the purposes of producing a greater amount of substrates for the reactions necessary for SIRT1 activation, boosting the beneficial action of resveratrol. The administration of the composition according to the invention may take place both directly and by the substantially simultaneous administration of the active ingredients.

The present invention also relates to the use of the composition as a food supplement or as a medicament in itself or as a cosmetic for topical use.

Detailed description of the invention

Unlike previous formulations, the present invention proposes a strengthening system for SIRT1 activation, providing the chemical substrates necessary for greater activation by resveratrol and therefore greater beneficial activity of SIRT1.

Within the scope of the present invention it has surprisingly been found that a composition comprising resveratrol, L-tryptophan, L-aspartic acid and β-nicotinamide adenine dinucleotide hydrate is able to increase SIRT1 activity in various tissues, increasing the effect of resveratrol.

The studies carried out were based on the laws of pharmacokinetics to assess the best quantitative composition of resveratrol, L-tryptophan, L-aspartic acid and β- nicotinamide adenine dinucleotide hydrate starting from various compositions (in percent) of the four components mixed in a single solution containing salt solution 0.9% NaCI): and Solutol (BASF, Wyandotte, Ml, USA) in a ratio of 7:3 and injected into rats (average weight 250-350 grams) intraperitoneally (i.p.) in a dose of 10 mg/Kg of body weight for resveratrol, 0.87 mg/Kg of body weight for L-tryptophan, 0.175 mg/Kg of body weight for aspartic acid and 0.37 mg/Kg of body weight for β-nicotinamide adenine dinucleotide hydrate. All the substances were provided by Sigma Chemical, St. Louis, MO, USA.

The principles of pharmacokinetics state that a compound, if administered orally, in order to reach systemic circulation must dissolve in the lumen of the alimentary canal, pass through the gastrointestinal mucous and pass beyond the liver after having been guided into the portal system. Each of these stages may limit the amount of drug able to be distributed within a patient's body: this concept is expressed by the term "oral bioavailability", which defines the percentage of the administered dose which effectively enters systemic circulation and is able to be distributed to the entire organism. A substance administered intraperitoneally, which is a route commonly used in experimental and toxicological medicine, is generally absorbed by portal circulation and must pass through the liver before reaching other organs, similarly to oral administration. The dose is increased if administered orally since the passage through the gastric tract has to be included. By calculating the difference in body mass between a human being and a test animal and the doses of the following compounds used commonly on the market, the following doses of a preferred composition were developed in the experimental tests: resveratrol 100 mg, L-tryptophan 17.5 mg, aspartic acid 35 mg and β-nicotinamide adenine dinucleotide hydrate 7.5 mg, these being doses at which it was possible to provide the following composition which proved to be effective (in percent):

resveratrol 50 - 70%, preferably 62%

L-tryptophan 8 - 15%, preferably 11%

aspartic acid 17 - 24%, preferably 22%

β-nicotinamide adenine dinucleotide hydrate 3 - 7%, preferably 5%

the percentages are expressed with reference to the total percentage of the active ingredients. The composition according to the present invention, in addition to the above-mentioned active ingredients, may also contain additives and vehicles which are pharmaceutically tolerable or which are commonly used in food supplements and/or cosmetic products.

Experiment 1

Measurement of SIRT1 activity in cerebral hippocampus neurons in four groups of male Sprague Dawley (SD) rats (250-350 grams).

Group 1- control (n=5). No treatment. Measurement based on SIRT1 activity.

Group 2 - resveratrol (n=6). Treatment with resveratrol injected i.p. in doses of 10 mg/Kg of body weight. Measurement of SIRT1 activity from 1 hour after treatment. Group 3 - vehicle (salt solution + Solutol) (n=5). Treatment via i.p. injection of the vehicle alone necessary for solubilisation of the compound in a dose of 10 mg/Kg of body weight. Measurement of SIRT1 activity from 1 hour after treatment.

Group 4 - (n=8). Treatment with the composition of the invention, injected i.p. as reported above. Measurement of SIRT1 activity from 1 hour after treatment.

Study results phase I

The results of the study have shown how resveratrol injected alone was able to increase SIRT1 activity by 30% compared to the control and vehicle groups (p<0.05) in cerebral tissue. By contrast, the composition according to the invention increased SIRT1 activation by 60% compared to the control and vehicle groups (p<0.01) and by 30% compared to the group of rats treated only with resveratrol (p<0.05), practically doubling the effect of resveratrol in SIRT1 activation (Fig. 1).

RATIONALE OF STUDY PHASE II

In light of these results, we tested the neuroprotective effect of the compound with regard to cerebral ischemia on the basis of previous data obtained for resveratrol (Delia Morte et al., 2009), where we demonstrated how resveratrol, thanks to its SI RT1 -activating action, was able to protect the brain against ischemic damage.

Experiment 2

A test of induction of cerebral ischemia was carried out in four groups of male SD rats (250-350 grams).

Group 1 - sham control, cardiac arrest (CA) (n=5) - Rats subjected to sham-type surgery.

Group 2 - ischemia test/control vehicle (n=5) - 8 minutes of CA were induced 48 hours after injection of the vehicle (salt solution and Solutol 2 ml/Kg of body weight). Group 3 - resveratrol + CA (n=8) - resveratrol was injected i.p. at a dose of 10 mg/Kg of body weight 48 hours before induction of 8 minutes of CA.

Group 4 - composition of the invention (n=8). The components of the above compound were solubilised in the doses stated above and were proven to be able to activate SIRT1 , injected i.p. in a single dose 48 hours before induction of 8 minutes of CA.

The reference period was selected to be 48 hours since this is the period in which ischemic preconditioning has the greatest effect and in which resveratrol is able to mimic the neuroprotective effect of said ischemic preconditioning (Delia Morte D. et al., 2009).

Study results phase II The histopathological damage in the CA1 zone of the hippocampus was assessed seven days after ischemic reperfusion. The results of the study demonstrated how, after cerebral ischemia, the number of living neurons in the CA1 zone of the hippocampus had reduced drastically compared to the control group (p<0.01). Resveratrol was able to increase the number of living neurons in treated rats by 200 % compared to the ischemia test group (p<0.02). The new tested complex (resveratrol, tryptophan, aspartic acid, β-nicotinamide adenine dinucleotide hydrate) increased the number of living neurons by 350% compared to the ischemia test group (p<0.01) and by 130% compared to resveratrol alone (p<0.02), thus demonstrating a rather powerful neuroprotective effect with regard to cerebral ischemia (Fig. 2).

In conclusion, the present preliminary data clearly demonstrates how the coordinated use of resveratrol, L-tryptophan, aspartic acid and β-nicotinamide adenine dinucleotide hydrate solubilised in a single complex is more effective at increasing SIRT1 activity and consequently at protecting against cerebral ischemia compared to resveratrol used alone in the same doses. The use of such a compound may have a beneficial and cosmetic purpose by utilising the anti-ageing properties of SIRT1 activation.

The present invention also relates to the use of the composition in the pharmaceutical, nutritional and cosmetic fields, in the latter case by topical application. The composition may be used for the prevention of age-related diseases, in particular cardiovascular and neurodegenerative diseases, and of systemic and cutaneous signs of ageing, especially caused by UVB.

Materials and methods

Measurement of SIRT1 activity

To measure SIRT1 activity, cerebral tissue was removed from the hippocampus of rats 1 hour after pre-treatment with resveratrol and the composition of the invention. The nuclear extract was fractionated using the technique described previously in detail by Raval and colleagues (Raval, 2006). The enzyme activity of SIRT1 was measured using the kit based on the fluor de Lys-SIRT1 substrate peptide (BioMol International, Plymouth Meeting, PA, USA), able to measure the enzyme activity of SIRT1 via fluorescence. The sensitivity of the activation of the suramin was considered as the enzyme activity of SIRT1.

Cardiac arrest (CA)

As described before (Dave, 2004), CA was induced by disconnection of the ventilator from the endotracheal tube. Eight minutes after the onset of asphyxia, resuscitation measures were implemented: administration of epinephrine intravenously (i.v.) (0.0005 mg/kg) and sodium bicarbonate (1 mEq/kg i.v.) followed by mechanical ventilation with supply of 100% 0 ₂ and cardiac massage at a frequency of 200/min until average arterial pressure was 60 mmHg and cardiac pulse rate was maintained spontaneously for more than 10 seconds. Once the animals were haemodynamically stable with spontaneous breathing, generally 10 to 15 minutes after restoration of spontaneous circulation, the catheters were removed and the animals were extubated, although 100% 0 ₂ continued to be supplied via a face mask. Body and brain temperatures were maintained at 37 °C using a heat lamp for one hour. The animals belonging to the control group (sham CA) underwent the surgical procedure similarly to the CA group, except for the induction of the CA. Temperature and body weight were monitored up to the seventh day and there were no considerable differences between the groups (Table 1).

Table 1

Group Variable Cardiac arrest

Before 10 min after

Sham ACA Body weight 312 ± 30

(n = 5) H 7.45 ± 0.01

PCO2 mm Hg 37.14 ± 1.32

pC-2 mm Hg 123.7 ± 7.29

Plasma 119 ± 15

Vehicle + ACA Body weight 315 ± 14

(n = 5) PH 7.46 ± 0.009 7.4+ 0.02

pCO∑ mm Hg 35.37 ± 1.39 32.07 ± 0.61

PO2 mm Hg 125.4± 9.06 275.58 ± 53.55

Plasma 117 ± 14.

Resveratrol 10 Body weight 297 ± 21

mg/Kg + ACA pH 7.48 ± 0.08 7.39 ± 0.01

PCO2 mm Hg 36.6 ± 1.17 34.3± 1.6

(n = 8) p0 ₂ mm Hg 136.3 ± 10 338 ± 66 ^*

Plasma 1 11 ± 12

Compound 10 Body weight 305 ± 10

mg/Kg + ACA pH 7.45 ± 0.01 7.37 ± 0.02

PCO2 mm Hg 35.4± 0.8 33.3± 1.6

(n = 8) pO _∑ mm Hg 130.9 ± 6.31 262.48 ± 58

Mortality 18% Plasma 1 12 ± 17

glucose mg/dl

Histopathology

Seven days after the CA, the rats were anaesthetised with isoflurane and perfused with a mixture of 40% formaldehyde, glacial acetic acid and methanol mixed at a ratio of 1 :1 :8 (Perez-Pinzon, 1997). The brains were thus removed from the skull and treated with paraffin; the coronal sections were cut to a thickness of 10 μιτι and stained by the haematoxylin/eosin method. The entire hippocampus was examined both the anterior and the posterior part. The number of normal neurons was counted inside the CA1 region of the hippocampus 3.8 mm behind the bregma. The neurons which showed cellular modifications relating to the ischemia were identified by: 1) nucleus eosinophilic cytoplasm, 2) dark colouration of the nuclear agglomerates, 3) eosinophilic colouration of the nucleole. For each group of rats subjected to ischemia, the neurons were counted over 18 lines per section, from the medial part to the lateral part along the entire CA1 region of the hippocampus.

Efficacy on neurodeqeneration with model of C. elegans

In C. elegans neurodegeneration may be induced by a genetic mutation in the "6 touch sensing neurons". This mutation induces hyperactivation of the MEC-4 channel Na ⁺ /Ca ²⁺ of the DEG/ENaC family (mec-4(d)). Neurodegeneration induced by (mec- 4(d)) shows numerous characteristics which are typical of neuronal death induced by ischemia/reperfusion including hyperactivation of the DEG/EnaC channel, intracellular increase in the concentration of Ca ²⁺ and swelling of the cellular body. The data shows the comparison between the control mec-4(d), resveratrol and the composition of the invention in the model of C. elegans mec-4(d) able to induce neurodegeneration. The composition of the invention was added at a concentration equal to 5μΜ (concentrations used previously in various in vitro studies) (Raval A et al., 2009) in culture dishes for C. elegans. C. elegans eggs were then added to the dishes. Neurodegeneration after treatment was assessed by counting the number of neurons still surviving after treatment with the compound at stage L4 of F0 and F1 generation compared to the number of neurons in mec-4(d), used as a control in our experiments. With regard to the treatment with resveratrol, the same concentrations used for our compound were used. For each experiment an average number of 250 to 350 animals was used. Our data (Fig. 3, in which the composition of the invention consistently yields results better than resveratrol, which in turn yields results better than the control) show that the compound is able to significantly increase (*p<0.05) the number of animals having 2, 3 and 4 living neurons compared to both the control and the animals treated with resveratrol, indicating a powerful neuroprotective effect.

Statistical analysis

All data is expressed as the mean of the values obtained. The variability caused by the standard error of the mean (SEM) was also assessed. The statistical validity of the data was examined using the ANOVA test followed by the Bonferroni test. A p<0.05 was considered to be statistically significant. TOXICITY TESTS

In support of the efficacy and of the non-toxicity of the composition according to the invention in our studies, toxicity tests were carried out on the individual components. For such tests, we proceeded on the basis of previous tests carried out by the manufacturer who had provided us with the compounds.

RESVERATROL

Acute toxicity

No data available from tests carried out

Skin irritation/corrosion

no data available

Severe ocular lesions/ocular irritation

no data available

Respiratory or skin sensitisation

May cause an allergic reaction on skin.

Mutagenic effect on embryonic cells

no data available

Carcinogenic effect

IARC: No component of this product present at a level greater than or equal to 0.1 % has been identified as a known or expected carcinogenic by IARC.

Toxicity for reproduction

no data available

Specific toxicity for target organs - one-time exposure

Inhalation - May irritate the airways.

Specific toxicity for target organs - repeated exposure

no data available

Risk in case of inhalation

no data available

Potential consequences for health

Inhalation May be harmful if inhaled. Causes irritation of the airways.

Skin May be harmful if absorbed through the skin. Causes skin irritation.

Eyes Causes severe ocular irritation.

Signs and symptoms of exposure

To the best of our knowledge, the chemical, physical and toxicological properties have not been studied in depth.

further information RTECS: CZ8987000

L-TRYPTOPHAN

Acute toxicity

DL50 oral - rat - > 16,000 mg/kg

Observations: Sensory organs: Sight: ptosis Behaviour: coma Information on nutrition and on overall metabolism: alterations: fall in body temperature

Skin irritation/corrosion

no data available

Severe ocular lesions/ocular irritation

no data available

Respiratory or skin sensitisation

no data available

Mutagenic effect on embryonic cells

no data available

Carcinogenic effect

IARC: No component of this product present at a level greater than or equal to 0.1% has been identified as a known or expected carcinogenic by IARC.

Toxicity for reproduction

no data available

Specific toxicity for target organs - one-time exposure

no data available

Specific toxicity for target organs - repeated exposure

no data available

Risk in case of inhalation

no data available

Potential consequences for health

Inhalation May be harmful if inhaled. May cause irritation of the airways.

Skin May be harmful if absorbed through the skin. May cause skin irritation.

Eyes May irritate the eyes.

Signs and symptoms of exposure

The FDA (Food and Drug Administration) and the Centre for Disease Control have established that there is a link between L-tryptophan and a potentially life-threatening haematic disorder called eosinophilia-myalgia syndrome characterised by severe muscular and joint pain, swelling of the upper and lower limbs, skin rashes and sometimes fever. It is characterised by severe eosinophilia, a haematic disorder in which the white blood cells increase to abnormal levels. L-tryptophan is present in nature in many food products and the studies carried out have not established whether it is the product itself or an impurity introduced during the preparation or distribution process which is the cause of such problems.

further information

RTECS: YN6130000

L-ASPARTIC ACID

Acute toxicity

DL50 oral - rat - 5,000 mg/kg

DL50 dermal - on rabbits - 5,000 mg/kg

Skin irritation/corrosion

Skin - on rabbits - No skin irritation

Severe ocular lesions/severe ocular irritation

Eye irritant

no data available

Respiratory or skin sensitisation

no data available

Mutagenic effect on embryonic cells

no data available

Carcinogenic effect

IARC: No component of this product present at a level greater than or equal to 0.1% has been identified as a known or expected carcinogenic by IARC.

Toxicity for reproduction

no data available

Specific toxicity for target organs - one-time exposure

no data available

Specific toxicity for target organs - repeated exposure

no data available

Risk in case of inhalation

no data available

Potential consequences on health

inhalation

May be harmful if inhaled. May cause irritation of the airways.

Eyes

Causes serious ocular irritation. Signs and symptoms of exposure

To the best of our knowledge, the chemical, physical and toxicoiogical properties have not been studied in depth,

further information

RTECS: CI9098500

β-nicotinamide adenine dinucleotide hydrate

Acute toxicity

DL50 oral - rat - 3,500 mg/kg

Irritation and corrosion

no data available

Sensitisation

no data available

Continued exposure

IARC: No component of this product present at a level greater than or equal to 0.1 % has been identified as a known or expected carcinogenic by IARC.

Signs and symptoms of exposure

To the best of our knowledge, the chemical, physical and toxicoiogical properties have not been studied in depth.

Potential consequences for health

Inhalation

May be harmful if inhaled. Causes irritation of the airways.

Eyes

Causes ocular irritation.

Target organs kidneys, eyes, liver

further information

RTECS: QS3675000