Reaction product of {mixture of [poly(1~4)chlorosulfonylphthalocyaninato-N29,N30,N31,N32]copper(Ⅱ) and [poly(1~3) chlorosulfonyl (tribenzo[b,g,l]pyrido[2,3-q]-5,10,15,20-tetraazaporphyrinato-N21,N22,N23,N24)] copper(Ⅱ) and [poly(1~2) chlorosulfonyl (dibenzo[b,g(or b,l)]dipyrido [2,3(or 3,2)-l,q(or g,q)]-5,10,15,20-tetraazaporphyrinato-N21,N22,N23,N24)] copper(Ⅱ) and [monochlorosulfonyl (benzo[b]tripyrido [2,3(or 3,2)-g,l,q]-5,10,15,20-tetraazaporphyrinato-N21,N22,N23,N24)]copper(Ⅱ) }and 2-[4-(2-aminoethylamino)-6-(benzylamino)-1,3,5-triazin-2-ylamino]benzene-1,4-disulfonic acid, and ammonia water and sodium chloride

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

50

Additional information

Assessment of the Toxicokinetic Behaviour

 

Copper, phthalic anhydride-2,3-pyridinedicarboxylic acid-urea reaction products complexes, aminosulfonyl [[2-[[4-[(2,5-disulfophenyl)amino]-6-[(phenylmethyl) amnino]-1,3,5-triazin-2-yl]amino]ethyl]amino]sulfonyl sulfo derivs., sodium salts (EC-No. 700-815-8)

 

There are no studies available in which the toxicokinetic properties of thereaction productCopper, phthalic anhydride-2,3-pyridinedicarboxylic acid-urea reaction products complexes, aminosulfonyl [[2-[[4-[(2,5-disulfophenyl)amino]-6-[(phenylmethyl) amnino]-1,3,5-triazin-2-yl]amino]ethyl]amino]sulfonyl sulfo derivs., sodium salts were investigated.

 

Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of thereaction productwas conducted based on the relevant available information.

 

This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties according to‚ Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance‘ (ECHA, 2012).

 

Thereaction product(molecular weight of an UVCB is not available, but estimated to 1220 g/mole given for a possible constituent when l=1, m=1, n=1, and when 1 pyridine ring is present in the Cu-phthalocyanine moiety) is a blue powder, which is very soluble in water (>= 403 g/L).The log Po/w is < -4.6 (estimation method, see chapter 4.7 partition coefficient),indicating the good hydrophilie of thereaction product.

As the substance has shown no melting (or boiling) point below the temperature at which decomposition started, i.e. 300°C, the test on vapour pressure was not performed. Calculation was not considered either due to lack of experimental data for boiling point.

 

Absorption

 

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

 

Oral

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2012). As the molecular weight of the smallest compound of the complex UVCBreaction productis estimated to 1220 g/mol absorption of these large molecules in the gastrointestinal tract is not likely.

But in the gastrointestinal tract (GIT), metabolism prior to absorption via enzymes of the microflora may occur as the oral toxicity studies indicate that absorption can be seen in bueish feces and urine.

The available data on oral toxicity of the test substance isan acute oral toxicity study conducted to female rats 9 weeks old Crl:CD(SD) in accordance with the OECD test guideline 423. A dose of 2000 mg/kg was employed for the first and second administration to each three rats. As a result, there was no mortality, no body weight gain effects, or necropsy findings. Clinical signs were restricted to test substance mixed feces and chromaturia (blueish). In conclusion, the LD50 of thereaction productin rats is estimated to be 2000 mg/kg or above under the conditions of this study.

In the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity ScreeningTest in ratsthereaction productshowed increase in globule leukocyte in the glandular stomach in high dose males; in high dose animals effects were observed on haematology (platelet count, numbers of neutrophils and lymphocytes, total cholesterol, plasma glucose and plasma triglyceride levels). Pigment-laden macrophages were noted in the stomach of high dose males and in the GI-tract, lungs and lymph nodes of mid and high dose rats, but the toxicological relevance is unclear. Based on the effects observed in the high dose group (globule leucocyte number, haematology and clin biochem), the NOAEL in this study is considered to be 250 mg/kg bw/day for parental animals of both sexes under the test conditions (OECD422 supporting study; see chapter 7.5.1 repeated dose oral). No reproduction toxicity and no developmental toxicity was observed.

 

The above described studies show that thereaction productreveals a low potential for toxicity after acute and repeated exposure, although no assumptions can be made regarding the absorption potential based on the experimental data.

In general, after oral ingestion, thereaction productwill undergo chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. It is assumed that copper phthalocyanines with different side chains are formed.

The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, based on the findings in the oral toxicity studies, it is evident that some absorption occurs in the gastro-intestinal tract.

It is assumed, that lipophilic cleavage products will be absorbed by micellar solubilisation whereas the hydrophilic products will readily dissolve into the gastrointestinal fluids and strongly dissociated substances are hardly absorbed. Completely ionized substances are from gastro-intestinal tract not absorbed.

In summary, the above discussed physical-chemical properties ofreaction productand the toxicity studies do not indicate rapid hydrolysis before its absorption. On the basis of the above-mentioned data, a low absorption of the parent substance is assumed.

 

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favours dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2012). As the molecular weight of thereaction productis much higher than 500 g/mol absorption of the UVCB by skin is not assumed.

 

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012).In an acute dermal toxicity study, a single dose level of 2000 mg/kgreaction productwas administered to Crl:CD(SD) rats (key study, see chapter 7.2.3 acute dermal toxicity). No signs of systemic toxicity were observed, indicating primarily a low dermal toxicity (the LD50 value of the test item is more than 2000 mg/kg body weight).

No skin irritation was observed in a dermal irritation test with New Zealand White rabbits(Acute dermal irritation test in the rabbit,see chapter 7.3.1 skin irritation).Therefore, an enhanced penetration of the substance due to local skin damage can be excluded.

 

Furthermore, no skin sensitisation potential was observed in 30 female mice using the LLNA study performed according to OECD 429(key study, see chapter 7.4.1 skin sensitisation). No abnormalities in body weight, lymph node weight or clinical signs were observed in any of the animals.

 

Overall,due to the experimental low dermal toxicity, the high molecular weight (>100) and the fact that the substance is not irritating nor sensitising to skin implies that dermal uptake of thereaction productin humans is considered as very low.

 

 

Inhalation

 

In an acute inhalation toxicity study with dust thereaction productwas tested in Sprague-Dawley rats in the doses 2 and 5 mg/L. (key study; see chapter 7.2.2 inhalation toxicity study in rat). In the low dose group, no mortality was observed, whereas 1 male rat died in the high dose group the day after exposure. No clinical signs were observed in the low dose group. In the high dose group, sedation, deep respiration and laboured respiration until one day after exposure, which disappeared on day 2 after exposure. In the low dose group, body weight losses were noted in all animals on day 1 after exposure, in 3 males on day 3 after exposure and in 1 male on day 7 after exposure (as compared with body weight before exposure). In the high dose group, body weight losses were noted in all animals on day 1 after exposure and in 4 males on day 3 after exposure (as compared with body weight before exposure). All animals gained their body weights at the end of the observation period (14 days after exposure). No macroscopic abnormalities were noted in any surviving animal at the end of the observation period. Based on these results, the LC50 of thereaction productfor both sexes of Sprague-Dawley rats in this study is therefore more than 5 mg/L.

 

Thereaction productCopper, phthalic anhydride-2,3-pyridinedicarboxylic acid-urea reaction products complexes, aminosulfonyl [[2-[[4-[(2,5-disulfophenyl)amino]-6-[(phenylmethyl) amnino]-1,3,5-triazin-2-yl]amino]ethyl]amino]sulfonyl sulfo derivs., sodium saltsdo not evaporate (see chapter 4.6 vapour pressure). Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not expected to be significant.

 

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2012).

Any lipophilic compound may be taken up by micellular solubilisation, but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.

Hydrolases present in the lung lining fluid may also hydrolyse the substance, hence making the resultingcleavage productsavailable for respiratory absorption. Due to the high molecular weight of the substance, absorption is driven by enzymatic hydrolysis of the sulfonyl derivatives to the respective metabolites and subsequent absorption.

Therefore, respiratory absorption ofreaction productis considered not to be higher than absorption through the intestinal epithelium.

Overall, a systemic bioavailability of thereaction productin humans is considered likely after inhalation of dust but not expected to be higher than following oral exposure.

 

Accumulation

Highly hydrophilic substances as is the case for thisreaction product,generally tend to be excreted via the kidneys. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. (ECHA, 2012).

However, as absorption of thereaction productis considered to be low, the potential of bioaccumulation is low as well.

Nevertheless, as further described in the section metabolism below, the sulfonyl derivatives of the reaction product will undergo hydrolysis, leading to the respective cleavage products.

The log Pow and the water solubility of the cleavage products are unknown. Consequently, accumulation cannot be predicted. But the available information from the toxicity studies indicates that no significant bioaccumulation of the parent substance and cleavage products in adipose tissue is anticipated.

 

Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2012).

Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rate of absorption.

As discussed above absorption of thereaction productis considered low based on its physico-chemical characterisation with a high solubility in water and high molecular weight.

Nevertheless, thereaction productwill undergo chemical changes as a result of slow enzymatic hydrolysis, leading to different cleavage products of the sulfonyl derivatives.

Overall, the available oral toxicity studies indicate that thereaction productand/or its cleavage products are distributed in the organism which can be observed through some effects like haematology.

 

Metabolism:

 

Thereaction productconsists of several sulfonyl derivatives that can be hydrolysed by hydrolases to numerous cleavage products.

Depending on the route of exposure, hydrolase-catalysed hydrolysis takes place at different places in the organism: after oral ingestion, the sulfonyl derivatives undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

Metabolism of thereaction productis quite complex due to the complexity of the product there are numerous cleavage products possible. In general cleavage products with physico-chemical properties like low molecular weight, low log Pow, and good solubility in water are easily absorbed and can either remain unchanged or may further be metabolized or conjugated (e.g. glucuronides, sulfates, etc.) to polar products that are excreted in the urine.

In the various studies of acute and combined repeated dose toxicity some minor effects were observed that disappeared at the end of the observation periods. It shows that thereaction productis absorbed, metabilized and the excreted.

The above described studies show that thereaction productreveals a low potential for toxicity after repeated exposure. Based on these data and on the properties of thereaction productcharacteristics a low absorption is assumed.

 

Excretion:

 

On the basis of the oral toxicity study in which thereaction productand/or its cleavage products were seen in the faeces and urine (bueish faeces and urine) excretion via faeces and urine is assumed to be alike.

Assuming that hydrolysis of thereaction producttakes place the breakdown products will occur in the body. They may either further be metabolized or conjugated to polar products (e.g. glucuronides, sulfates, etc.) or excreted unchanged via urine and faeces.