Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference

Toxicokinetics data from studies conducted under in vitro and in vivo conditions suggests that the test substance, C12-16 ADBAC, has a low bioaccumulation potential and only a small fraction of the test substance is likely to be absorbed and distributed over the body. Therefore, a 10% absorption factor was considered for the chemical safety assessment for both oral as well as dermal routes as a worst-case approach even though with the most relevant and valid studies, a 1% dermal absorption would be a high estimate. An absorption of 100% was considered for the inhalation route.

The available data for the test substance on dermal absorption does not allow the quantification of the dose which was absorbed after dermal application. However, based on the radioactivity recovered at the skin application site after removal of the stratum corneum layers (6.5-8.7% of the dose) and the ionic nature of the test substance, it can be anticipated that the dermal absorption is not different from the oral one (10%). The primary effect involves disruption of the cytoplasmic membrane causing cell damage or lyses of the cell content. Due to adherence to negatively charged surfaces of the apolar alkyl chain, ADBAC substances will not easily pass biological membranes. Dermal uptake is therefore very limited at low, non-irritating concentrations.

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
50

ABSORPTION:  

Oral absorption  

Based on physicochemical properties:  

According to REACH guidance document R7.C (May 2014), oral absorption is maximal for substances with molecular weight (MW) below 500. Water-soluble substances will readily dissolve into the gastrointestinal fluids; however, absorption of hydrophilic substances via passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Further, absorption by passive diffusion is higher at moderate log Kow values (between -1 and 4). If signs of systemic toxicity are seen after oral administration (other than those indicative of discomfort or lack of palatability of the test substance), then absorption has occurred. 

C12-16 ADBACis an alkyl dimethyl benzyl ammonium chloride (ADBAC) type of cationic surfactant. It is a UVCB with majorly C12 to C16 alkyl chains with molecular weight ranging from 283.9 to 424.02 g/mol. The purified form of the substance is a crystalline, hygroscopic, sticky white solid. It has a moderate water solubility of 500-1000 mg/L at 20°C (based on CMC) and a low log Kow of 2.75 value, which was determined based on solubility ratios. 

Based on the R7.C indicative criteria, together with the fact that the test substance is cationic with a strong adherence potential to the negatively charged surfaces of the membranes, suggests that it is not expected to easily pass biological membranes.

Based on experimental data on read across substances:  

A study was conducted to determine the basic toxicokinetics of the test substance, C12-16 ADBAC (49.9% active in water with 99.4% radiolabelled purity), according to OECD Guideline 417, in compliance with GLP.In this study, Sprague-Dawley rats were treated with single and repeated oral doses (50 or 200 mg/kg bw) as well as a single dermal dose (1.5 or 15 mg/kg bw) of the radiolabelled test substance. Following single and/or repeated oral doses, the plasma, blood and organ radioactivity levels were essentially non-quantifiable, indicating a low oral bioavailability. The actual fraction of the oral dose absorbed was around 8% (urine and bile fractions). This was eliminated rapidly, essentially within a 48 to 72 h period. The majority of the oral dose was excreted in the faeces. At the high oral dose level only, quantifiable levels of radioactivity (2,386 to 23,442 ηg equivalent/g) were found in some central organs at 8 h post-dosing; otherwise, most of the dose was confined to the intestines, where their levels decreased over time and were all non-quantifiable by 168 h (i.e., 7 d). Only about 4% of the oral dose was eliminated in the bile in a 24 h period, of which about 30% during the first 3 h. Following a single dermal application, the plasma and blood radioactivity levels were non-quantifiable at nearly all time points. For the 1.5 mg/kg bw group, around 2 and 43% of the dose was eliminated in the urine and faeces, respectively, mostly within a 48-h period, suggesting that the dermal dose was highly absorbed via the skin. However, this apparent high absorption via the skin may have been due to the animal licking the test site. This is also supported by the finding that, after oral dosing, only about 4% was excreted via bile back to the intestine and 4% excreted via urine. If similar routes of excretion are expected for dermally absorbed doses, it would not be possible to find levels of 50% of applied doses in the intestine with only 2% excreted via urine. This indicates that about 50% of the dermally applied dose was taken up orally after all. According to the same oral kinetics, this leads to the 2% excretion in urine as indeed was observed. At 24 h post-dosing, most of the radioactivity was in the “stripped” skin (dermis/epidermis) application site (15.02/8.74% [male/female] and 33.8/24.2% of the dose for the high and low dose groups respectively) and intestines for both dose levels (5.76/8.32% and 5.61/7.79% of the dose for the high and low dose groups respectively), though some radioactivity was in the skin adjacent to the application site and minor traces were in the eyes (both most likely from cross-contamination due to grooming). At 168 h, levels in the application site of the individual animals of the low dose were 5.19 to 9.21% of the radioactive dose, suggesting the skin acted as a drug reservoir. In the stratum corneum of the application site, the levels of radioactivity were of similar magnitude in the different layers at each time point. For all tissues/organs, the radioactivity levels decreased over time. All data showed generally a low inter-animal variability. In addition, there was no evidence of gender differences. Under the study conditions and following oral administration the test substance was found to have limited absorption (ca. 10%), low distribution (below quantification limits within 4-7 d) and majorly excreted via faeces (ca. 80%). The results following dermal application are considered to be invalid, as the experiment suffered from design flaws, allowing for oral uptake from the skin after the 6 h exposure period (Appelqvist, 2006).

Further, a biocides assessment report available on the test substance by RMS Italy, concluded that the read across substance“is highly ionic and, therefore, it is expected not to be readily absorbed from the gastrointestinal tract or skin. The vast majority of the oral dose was excreted in the faeces (80%) as unabsorbed material (only about 4% of the oral dose was eliminated in the bile in a 24-hour period). The actual fraction of the oral dose absorbed was about 10%, based on the urinary mean value 3-4% (with a single peak value of 8.3%) and biliary excretion values (3.7-4.6%), as well as on the absence of residues in the carcass, as measured at 168 h. Excretion was rapid (within a 48 to 72-hour period). The radioactivity excreted in the urine was not associated with the parent compound, but with more polar metabolites which were not identified” (ECHA biocides assessment report, 2015).

In another study conducted according to EPA OPP 85-1, Sprague-Dawley rats (10 animals per sex per group) were treated with radiolabelled test substance, C12-16 ADBAC (30% active in water with 99.4% radiolabelled purity).Sprague-Dawley rats (10 animals per sex per group) were treated with a radiolabelled test substance. The study was conducted in four phases: a single low dose (10 mg/kg); a single high dose (50 mg/kg); a 14-d repeated dietary exposure with non-radiolabelled test substance (100 ppm) and a single low dose of radiolabelled (14C) test substance (10 mg/kg); and single intravenous dose (10 mg/kg). Following the single doses or the last dietary dose, urine and faeces were collected for 7 d. A preliminary study had indicated that insignificant 14CO2 was generated. Tissues, urine and faeces were collected and analysed for radioactivity and faeces were analysed by TLC, HPLC and MS for metabolites and parent compound. Following oral administration, radiolabelled test substance was rapidly absorbed, although in very limited amounts, consistent with its highly ionic nature. Residual 14C in tissues was negligible after administration by gavage both after single and repeated dosing, indicating low potential for bioaccumulation. After i.v. administration a higher amount of radioactivity (30−35%) was found as residue in the tissues. About 6−8% of orally administered test substance is excreted in the urine whereas, 87−98% was found in the faeces. Since no data on bile duct-cannulated rats are available, it was not possible to conclude if this radioactivity accounts exclusively for the unabsorbed test substance or not. However, the i.v. experiment showed that 20−30% was excreted in the urine and 44-55% in the faeces, suggesting that both the kidney and liver are capable of excreting test substance once absorbed and that absorption is higher than the % found in the urine after oral administration. Based on the urinary mean value 3-4% (with a single peak value of 8.3%) and biliary excretion values (3.7-4.6%), as well as on the absence of residues in the carcass, as measured at 168 h, it can be expected that the test substance absorption through the g.i. tract is about 10% (a conclusion not included in the study report; as assessed by the Italian Rapporteur Member state in the biocides dossier; ECHA biocides assessment report, 2015). Less than 50% of the orally administered test substance was found to be metabolised to side-chain oxidation products. Given the limited absorption of the test substance, the four major metabolites identified were expected to be at least partially formed in the gut of rats, apparently by microflora. No significant difference in metabolism between male and female rats or among the dosing regimens was observed. Repeated dosing did not alter the uptake, distribution or metabolism of test substance. Under the conditions of the study, the test substance was found to have limited absorption (ca. 10%; due to its ionic nature), negligible distribution (no bioaccumulation), and majorly excreted majorly via faeces (87-98%) following oral administration. However, following i.v. administration, it was found to be widely distributed (30-35%) in tissues and excreted both via faeces (40-55%) and urine (20-30%). Four major metabolites were identified, formed via oxidation of the alkyl chain (Selim, 1987).

Further, the biocides assessment report concluded that“the oral absorption can be considered to be approximately 10%, based on the 5-8% of the C12-16-ADBAC administered dose eliminated via urine and tissue residues (less than 1% of the administered dose 7 days after single and repeated oral dosing). More than 90% is excreted in the faeces and the pattern did not change after repeated doses. Although it was not possible to discriminate between unabsorbed/absorbed material, based on the chemical nature of the test substance, it can be anticipated that about 90% is present in faeces as unabsorbed material. The majority of C12-16-ADBAC metabolism is expected to be carried out by intestinal flora; the metabolites, which account for less than 60% of the administered dose, include hydroxyl- and hydroxyketo- derivatives of the dodecyl, tetradecyl and hexadecyl chains. No metabolite accounted for more than 10% of the total administered dose”(ECHA biocides assessment report, 2015).  

Assessment from biocides assessment report available on the test substance:  

As indicated above the biocides assessment reports available on the read-across substance C12-16 ADBAC indicated that given its ionic nature, C12-16 ADBAC was not expected to be readily absorbed from the gastrointestinal tract or skin. And based on the results from thein vivostudies with rats andin vitrostudies with human skin, an oral and dermal absorption value of 10% could be considered at non-corrosive concentrations (ECHA biocides assessment report, 2015). 

Conclusion:Overall, based on the available weight of evidence information, the test substance at non-corrosive concentrations can be expected to overall have low absorption potential through the oral route. Therefore, in line with the biocide assessment report and as a conservative approach a maximum oral absorption value of 10% can be considered for risk assessment.   

Dermal absorption  

Based on physicochemical properties:  

According to REACH guidance document R7.C (ECHA, 2017), dermal absorption is maximal for substances having MW below 100 together with log Kow values ranging between 2 and 3 and water solubility in the range of 100-10,000 mg/L. Substances with MW above 500 are considered to be too large to penetrate skin. Further, dermal uptake is likely to be low for substances with log Kow values <0 or <-1, as they are not likely to be sufficiently lipophilic to cross the stratum corneum (SC). Similarly, substances with water solubility below 1 mg/L are also likely to have low dermal uptake, as the substances must be sufficiently soluble in water to partition from the SC into the epidermis. 

The test substance is a crystalline, hygroscopic, sticky white solid with an MW exceeding 100 g/mol, moderate water solubility and an estimated log Kow above 2.This together with the fact that the test substance is cationic with a strong adherence potential to the negatively charged surfaces, suggests that the test substance at non-corrosive concentrations is likely to have a low penetration potential through the skin. 

At higher corrosive concentrations although there is a likelihood of exposure to the test substance due to disruption of the barrier properties of the skin, the likelihood of occurrence of these cases is expected to be minimal due to the required risk management measures and self-limiting nature of the hazard. Therefore, this scenario has not been considered further for toxicokinetic assessment.

Based on QSAR predictions:  

The two well-known parameters often used to characterise percutaneous penetration potential of substances are the dermal permeability coefficient (Kp[1]) and maximum flux (Jmax). Kp reflects the speed with which a chemical penetrates across SC and Jmax represents the rate of penetration at steady state of an amount of permeant after application over a given area of SC. Out of the two, although Kp is more widely used in percutaneous absorption studies as a measure of solute penetration into the skin. However, it is not a practical parameter because for a given solute, the value of Kp depends on the vehicle used to deliver the solute. Hence, Jmax i.e., the flux attained at the solubility of the solute in the vehicle is considered as the more useful parameter to assess dermal penetration potential as it is vehicle independent (Robert and Walters, 2007).  

In the absence of experimental data, Jmax can be calculated by multiplying the estimated water solubility (using WATERNT v.1.02) with the Kp values from DERMWIN v2.02 application of EPI Suite v4.11. The calculated Jmax values for the different carbon chains of the UVCB substance was determined to be range between 5.00E-07 to 8.50E-05 μg/cm2/h, leading to a weighted average value of 5.07E-06 μg/cm2/h. As per Kroeset al.,2004 and Shenet al. 2014, the default dermal absorption for substances with Jmax ≤0.1 μg/cm2/h can be considered to be less than 10%. Based on this, the test substance can be predicted to have low absorption potential through the dermal route.  

Based on experimental data:  

Following a single dermal application of the test substance, C12-16 ADBAC in the Appelqvist (2006) study, the plasma and blood radioactivity levels were non-quantifiable at nearly all time-points. For the 1.5 mg/kg bw group, around 2 and 43% of the dose was eliminated in the urine and faeces, respectively, mostly within a 48-h period, suggesting that the dermal dose was highly absorbed via the skin. However, this apparent high absorption via the skin may have been due to the animal licking the test site. This was also supported with the finding that, after oral dosing, only about 4% was excreted via bile back to the intestine and 4% excreted via urine. If similar routes of excretion are expected for dermally absorbed doses, it would not be possible to find levels of 50% of applied doses in intestine with only 2% excreted via urine. This indicates that about 50% of the dermally applied dose was taken up orally after all. Excretion in urine (2%) following dermal exposure was similar to that following oral exposure. At 24 h post-dosing, most of the radioactivity was in the “stripped” skin (dermis/epidermis) application site (15.02/8.74% [male/female] and 33.8/24.2% of the dose for the high and low dose groups respectively) and intestines for both dose levels (5.76/8.32% and 5.61/7.79% of the dose for the high and low dose groups respectively), though some radioactivity was in the skin adjacent to the application site and minor traces were in the eyes (both most likely from cross-contamination due to grooming). At 168 h, levels in the application site of the individual animals of the low dose were 5.19 to 9.21% of the radioactive dose, suggesting the skin acted as a drug reservoir. In the stratum corneum of the application site, the levels of radioactivity were of similar magnitude in the different layers at each time-point. For all tissues/organs, the radioactivity levels decreased over time. All data showed generally a low inter-animal variability. In addition, there was no evidence of gender differences (Appelqvist, 2006). Further, the biocides assessment report concluded that “The available data on BKC dermal absorption do not allow to quantify exactly the % of the dose which was absorbed after dermal application. However, due to the radioactivity recovered at the skin application site after removal of the stratum corneum layers (6.5-8.7% of the dose) and the ionic nature of the test item, it can be anticipated that the dermal absorption is not different from the oral one (10% at non corrosive concentration)”(ECHA biocides assessment report, 2015).  

An in vitro study was conducted to determine the rate and extent of dermal absorption of the test substance, C12-16 ADBAC (80.5% active; >99% radiolabelled purity), according to OECD Guideline 428, in compliance with GLP. The study was conducted with radiolabelled test substance at 0.03% and 0.3% concentrations, which was topically applied over split-thickness human skin membranes mounted into flow-through diffusion cells. Receptor fluid was pumped underneath the skin at a flow rate of 1.5 mL/hour. The skin surface temperature was maintained at approximately 32°C. A barrier integrity test using tritiated water was performed and any skin sample exhibiting a permeability coefficient (kp) greater than 2.5 x 10-3 cm/h were excluded from subsequent absorption measurements. The 14C- radiolabelled test substance was applied at an application rate of 10 mg/cm2. Absorption was assessed by collecting receptor fluid in hourly intervals from 0-6 h post-dose and then in 2-hourly intervals from 6-24 h post-dose. At 24 h post-dose, the exposure was terminated by washing and drying the skin. The stratum corneum was then removed from the skin by 20 successive tape strips. All samples were analysed by liquid scintillation counting. Under the conditions of the study, the mean absorbed dose and mean dermal deliveries were determined to be 0.05% (0.01 ηg equiv. /cm2) and 2.22% (0.07 ηg equivalent/cm2) of the applied dose for the low concentration test preparation, respectively, and 0.03% (0.01 ηg equivalent /cm2) and 2.16% (0.67 ηg equivalent/cm2) of the applied dose for the high concentration test preparation, respectively. The stratum corneum acted as a barrier to absorption, with the mean total unabsorbed doses (recovered in skin wash, tissue swabs, pipette tips, cell wash, stratum corneum and unexposed skin) of 96.80 and 94.68% of the applied dose for the low and high concentration test preparations, respectively. The maximum fluxes for the low and high doses were 0.12 ηg equivalent /cm2/h and 0.74 ηg equivalent /cm2/h, respectively, at 2 h (Roper, 2006).Based on literature evidence, substances with Jmax ≤ 0.1μg/cm2/h, can be expected to have low skin penetration potential and can be assigned a default skin absorption of <10% (Shenet al., 2014, Kroeset al.,2004). Further, the dermal absorption of the test substance was concluded in its biocides assessment report (by RMS Italy) to be 8.3%, which was obtained by summing up the radioactivity present in the receptor fluid (0.05%), at the application site (after 20 consecutive tape stripping procedures) and the one present in tape strips (n°6-20) (ECHA biocides assessment report, 2015). 

 

Another in vitro study was conducted to determine the dermal absorption of the test substance, C12 -16 ADBAC (25.5% active in water; radiochemical purity: >98%) according to a method comparable to OECD Guideline 427, in compliance with GLP. The dermal absorption and excretion study was conducted in rats following application of 0.4 mL of a 0.77% w/w solution of the test substance over approximately 20 cm2 of shaved skin, under a gauze patch for 72 h. After a single topical application of radio-labelled test substance, the total amount of radioactive substance was 16% in males (urine 0.8%, faeces about 9.9% and carcass about 5.3%) and 14% in females (urine about 0.7%, faeces about 6.1% and carcass about 7.0%). This was equivalent to a total mass of 24 µg equivalents (males) and 21 µg equivalents (females) absorbed per cm2(after a dose of approximately 3 mg). Most of the radio-labelled test substance (62.6%, males; 63.2%, females) was found in both the treated (48.0%, males; 45.1%, females) and the untreated (14.6%, males; 18.1%, females) skin after 72 h. The radioactive substance in the untreated skin may have been due to surface migration of the applied material from the perimeter of the treated area. The overall recoveries of radioactivity were acceptable for the experimental objectives of quantifying the absorption of radio-labelled test substance after a single dermal application. Under the study conditions, the findings indicate that the dermal absorption of the test substance is limited and most of the absorbed test substance is excreted in the faeces (Hallifax, 1991).

Additionally, a publication of Blank (1964) was identified which reported an in vitro study evaluating the dermal penetration of the test substance, C12-16 ADBAC (purity not specified) in normal excised human skin. From un-buffered aqueous solutions of the test substance ranging in concentration from 0.005 (1.7 ppm) to 0.1 M (34 ppm), no measurable amount penetrated the dermis of excised human skin within periods of 1 to 3 d at temperatures between 23 and 35°C. Lowering the pH of the contact solution up to pH 1.3 had no influence. However, at pH 10.5 to 12, the test substance could be recovered from the skin. At these levels, electrical conductivity indicated damage to the cutaneous barrier. Similarly, pre-treatment of skin at that pH caused damage to the skin and resulted in penetration of the test substance upon subsequent contact to test solutions. Also, damaging the skin by repeated stripping of the stratum corneum with pressure-sensitive tape resulted in penetration into the skin when stripped more than 10 times (Blank, 1964).

A corneal penetration was identified from literature sources, where single or multiple drops of radiolabelled test substance, C12 -16 ADBAC (0.03% radiolabelled purity) was instilled on the cornea of rabbits to determine the corneal penetration. The test substance was found in the palpebral and bulbar conjunctiva, corneal epithelium, stroma and endothelium. Single-drop administration resulted in high tissue levels in the anterior ocular tissues that were retained for up to 120 h. Multiple-drop administration led to accumulation in the epithelium to a greater degree than any other tissue. However, at no time did the test substance appear in the aqueous humour or any other tissue besides cornea and exposed conjunctivae (Green, 1986).

Assessment from biocides assessment report available on the test substance: 

As indicated above the biocides assessment reports available on the test substance C12-16 ADBAC indicated that given its ionic nature, C12-16 ADBAC was not expected to be readily absorbed from the gastrointestinal tract or skin. And based on the results from thein vivostudies with rats andin vitrostudies with human skin, an oral and dermal absorption value of 10% could be considered at non-corrosive concentrations (ECHA biocides assessment report, 2015). 

Conclusion:Overall, based on all the available weight of evidence information, the test substance at non-corrosive concentrations can be expected to have a low absorption potential absorption through the dermal route. As a conservative approach and in line with the biocide assessment report a maximum dermal absorption value of 10% can be considered for risk assessment.  

Inhalation absorption  

Based on physicochemical properties:  

According to REACH guidance document R7.C (ECHA, 2017), inhalation absorption is maximal for substances with VP >25 KPa, particle size (<100 μm), low water solubility and moderate log Kow values (between -1 and 4). Very hydrophilic substances may be retained within the mucus and not available for absorption. 

The test substance, because of its crystalline, hygroscopic, sticky white solid physical state and relatively low vapour pressure of < 5.8E-3 Pa at 25°C, will not be available as vapours for inhalation under ambient conditions. Therefore, the substance will neither be available for inhalation as vapours nor as aerosols. In the case of spraying applications, coarse droplets would be formed which typically settle on the ground and result in a very lower inhalable or respirable fraction. Of the inhalable fraction, due to the droplet size and the moderate water solubility, almost all droplets are likely to be retained in the mucus and will not be available to reach the deeper lungs. The deposited droplets in the upper respiratory tract are expected to be absorbed in a relatively slower rate compared to the deeper lungs due to differences in vascularity. Some amounts of these deposited droplets are also expected to be transported to the pharynx and swallowed via the ciliary mucosal escalator. Therefore, the systemic uptake of the test substance via the respiratory route can be considered to be similar to the oral route.

Conclusion: Based on all the available weight of evidence information, together with the fact that the test substance is cationic with an adherence potential to the negatively charged surfaces, the test substance at non-corrosive concentrations can be expected to have a low to moderate absorption potential through the inhalation route, depending on the droplet size. Therefore, a value of 50% can be considered for the risk assessment.           

.  

METABOLISM:  

Based on experimental data on test substances:  

As discussed in the Selim, 1987 study, less than 50% of the orally administered C12-16 ADBAC is metabolised to side-chain oxidation products. Given the limited absorption of the test substance, the four major metabolites identified may be at least partially formed in the gut of rats, apparently by microflora. The metabolites, which account for less than 60% of the administered dose, include hydroxyl- and hydroxy keto- derivatives of the dodecyl, tetradecyl and hexadecyl chains. No metabolite accounted for more than 10% of the total administered dose. No significant difference in metabolism between male and female rats or among the dosing regimens was observed. Repeated dosing did not alter the uptake, distribution or metabolism of the test substance (Selim, 1987). 

Based on QSAR modelling: 

The OECD Toolbox (v.4.4.1) and FAME 3were used to predict the first metabolic reaction, since the rat liver S9 metabolism simulator performs predictions for salts, while SMARTCyp and MetaPrint2D are not powered enough for this type of substance. The second simulator of the OECD Toolbox (in vivorat metabolism simulator) was not used as it does not consistently perform predictions for salts. As per the rat liver S9 metabolism simulator, the major constituents are primarily predicted to undergo ω or ω-1 aliphatic hydroxylation reactions. Similar results were found with FAME 3 metabolism simulation tool (which currently covers only CYP metabolism). See the table in the CSR for the reaction sites. For further details, refer to the read-across justification.

Overall, similar reactive sites were predicted for other TMACs and ADBACs from the category. 

Conclusion:Based on all the available weight of evidence information, the test substance is considered to be primarily metabolised by alkyl chain hydroxylation, which is carried out by the intestinal flora.  

DISTRIBUTION 

Based on physico-chemical properties: 

According to REACH guidance document R7.C (ECHA, 2017), the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores, although the rate of diffusion for very hydrophilic molecules will be limited. Further, if the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Identification of the target organs in repeated dose studies is also indicative of the extent of distribution. 

Generally given the ionic nature of the test substance, the test substance is not likely to readily partition across the blood membranes into the different organs, leading to an overall low distribution potential. Moreover, even if the test substance distributes to a certain extent, it is not expected to bioaccumulate based on the experimentalBCF values of C12-16 ADBAC(see section 4.3 of the CSR). 

Based on experimental data on read across substances: 

As discussed above, in the Appelqvist, 2006 study, quantifiable levels of radioactivity (2,386 to 23,442 ηg equivalent/g) were found in some central organs at 8 h post-dosing at 200 mg/kg bw; otherwise, the vast majority of the dose was confined to the intestines, where their levels decreased over time and were all non-quantifiable by 168 h (i.e., 7 d). In the Selim, 1987 study, residual 14C in tissues was negligible after administration by gavage both after single and repeated dosing, indicating low potential for bioaccumulation. However, following i.v. administration, it was found to be widely distributed (30-35%) in tissues (Selim, 1987).  

 

A couple of studies were also identified from literature sources (Bogs, 1971; Cutler, 1970):

The Bogs (1971) article reported a study evaluating the distribution of the test substance, C12-16 ADBAC (purity not specified) inside the body of rabbits, cats and dogs. A single high dose (approximately 1 mL of 15% solution of the test substance in water/kg bw of animals, which is equal to about 10 times the lethal dose) was administered by oral, rectal and intramuscular route. Within a few minutes, the animals died, and the test substance concentrations were measured locally at the sites of dosing, in blood, liver and kidneys. It was concluded that only a small fraction is absorbed and distributed in the body. Less than 1.5% of the applied dose was found in the organ investigated (sites of dosing, blood, liver and kidneys), of which the major part was found in the liver (Bogs, 1971).

The Cutler (1970) article reported studies conducted in rat and Beagle dogs, which compared the application of test substance, C12 -16 ADBAC (purity not specified) in both milk and water as vehicle. Rats received 50 and 100 mg/kg bw/day for 12 weeks, and dogs 12.5, 25 and 50 mg/kg bw/day for 52 weeks. Depression in weight gain was observed in rat receiving 100 mg/kg bw/day in the water, but not in milk. Mortality occurred in dogs at 25 and 50 mg/kg bw/day in the water, but not in milk. The 12.5 mg/kg bw/day dose level was well tolerated (Cutler, 1970).

Conclusion:Based on all the available weight of evidence information, the test substance is expected to have a low distribution and bioaccumulation potential.  

EXCRETION: 

Based on physicochemical properties: 

Given the expected low absorption potential of the test substance which is due to its ionic nature and physico-chemical properties, it can be expected to be primarily excreted through faeces. 

Based on experimental data on read across substances: 

Based on the evidence from the available oral studies (Appelqvist, 2006; and Selim, 1987), the test substance is primarily expected in faeces (>90%) and less via urine (<10%). 

Conclusion:Based on all the available weight of evidence information, the test substance is expected to be primarily excreted via faeces.  


[1] Log Kp = -2.80 + 0.66 log kow – 0.0056 MW 

Reason / purpose for cross-reference:
data waiving: supporting information
Reference

Based on the results of thein vivoskin and eye irritation studies, the test substance is considered to be corrosive to skin and eyes.   

Endpoint conclusion:
adverse effect observed (corrosive)
Endpoint conclusion:
adverse effect observed (irreversible damage)
Endpoint conclusion:
no study available

Skin

Study 1:A study was conducted to determine the skin irritation/corrosion potential of the test substance, C12-16 ADBAC (50% active in water) according to the method 'Transport of dangerous goods, special recommendations relating to Class 8, United Nations handbook, 1977'. In this experiment, 0.5 mL of an undiluted test substance (50% active) was applied under occlusive dressing to the skin of 1 rabbit for 3, 30, 60 min and 4 h. The skin was washed with water upon removal of the dressing. Observations were recorded at 24, 48 and 72 h. A confirmatory study was performed with 3 min or 1 h applications in 3 rabbits each. In the main study, no dermal reactions were observed at any of the 6 sites after 3 min application. Moderate erythema (mean score: 2.6) with slight oedema (mean score: 1.9) at 4 sites and areas of skin necrosis at the other 2 sites were observed following 1 h application (Primary irritation index PII: 3 min: 0; 60 min: 4.5). Under the conditions of the study, the test substance solution was considered to be corrosive to rabbit skin (Liggit, 1982).

Study 2:A study was conducted to determine the skin irritation/corrosion potential of the test substance, C12 -16 ADBAC (80% active), according to Federal Hazardous Substances Labelling Act. The experiment was performed on rabbits. The undiluted test substance (80% active) was applied on intact and abraded skin sites using occlusive patches for an exposure period of 24 h. The skin was then observed for erythema and edema formation and the scoring was done according to the Draize, Woodland and Calvery scoring system at 24 and 72 h from the onset of exposure. Severe erythema and edema were observed in all the test animals at both the abraded and intact sites. The mean Primary Irritation Index (PII) of the test substance was calculated to be 6.29 and the mean values of erythema and edema were 3.33 (intact skin site), 3.5 (abraded skin site), 2.66 (intact skin site) and 3 (abraded skin site). Based on the results of the study, the test substance is considered to be corrosive to rabbit skin (Wallace, 1975).

Study 3:A study was conducted to determine the skin irritation/corrosion potential of the test substance, C12-16 ADBAC (purity not specified) according to the method 'U. S. Federal Register, Vol. 41, No. 188, P. 42572’. The experiment was performed on rabbits. Six animals were treated with 0.5 mL of the test substance for 4 h under occlusive conditions. As the test proved positive for corrosion after 4 h, it was repeated in a different group of animals for an exposure period of 60 min and then for an exposure period of 3 min. Under the test conditions, the substance was corrosive to rabbit skin (Sugar, 1981).

Study 4:A study was conducted to determine the skin irritation/corrosion potential of the test substance, C12-16 ADBAC (purity not specified) according to OECD Guideline 404. The skin of albino rabbit was used in this experiment. A single 24 h, occluded application of the test substance (undiluted) to the intact and abraded skin of six rabbits produced necrosis with blanching extending beyond the entire site and severe oedema. Forty-eight hours after patch removal, each site and beyond was coriaceous and slight oedema was noted. No further observations were made. Corrosive effects were noted in all 6 rabbits. Under the study conditions, the test substance was corrosive to rabbit skin (Anspach, 1976).

Study 5:A study was conducted to determine the skin irritation/corrosion potential of the test substance, C12-16 ADBAC (25.5% active) according to a method similar to OECD Guideline 404, in compliance with GLP. The experiment was performed with a 25.5% active test substance. The objective of this study was to define a clear "non-irritant" level of administration and the maximum tolerated test concentration (irritancy, but not severe irritancy, corrosivity, toxicity or mortality) following a single topical administration to Wistar rats, and thereby select dosages for absorption, distribution and excretion study in the same strain of rat. Four groups of five male and five female Wistar rats were treated with 240 mm3 aliquot of 2.55, 1.28, 0.77 and 0.26% w/v test substance. The test site was protected by an Elizabethan collar for a period of 72 h following administration. Under the conditions of this study, the 'threshold of irritancy' of the test substance in distilled water was between 0.26 and 0.77% w/v, and the 'maximum tolerated' concentration was slightly more than 2.55% w/v. The lowest tested concentration of 0.26% w/v was non-irritant to rabbit skin (Cummins, 1991).

Study 6:A study was conducted to determine the skin irritation/corrosion of the test substance, C12-16 ADBAC (0.1% active in water) according to OECD Guideline 404. The experiment was performed to assess albino rabbits (strain not specified). Under the study conditions, a 0.1% aqueous solution of the test substance was not irritating to rabbit skin (following 24 h exposure under occluded conditions) (Hixson, 1968).

Additional irritation studies were identified for the test substance, C12-16 ADBAC (purity not specified) from literature sources. These studies were conducted with 0.1 to 1% active test substance in water in rabbits and guinea pigs. When applying 0.5 mL of the test substance on rabbit skin, concentrations of 1% or greater induced skin reactions, while 0.1% was not irritating. Exposure for 24 h to 0.1% aqueous test solution was not irritating to guinea pig skin, while the same exposure regime of 0.3% concentration caused irritation in rabbits. Also, 0.5 mL of a 0.5% aqueous test solution on the skin of nine rabbits for 24 h under the occlusive patch, resulted in barely perceptible erythema in one animal and no reactions in the others. In another study, 0.3% test solution was tested according to the same protocol. Skin irritation was not observed in any of the nine rabbits. A 0.1% aqueous solution of the test substance was applied to the skins of rabbits under plastic wrap for 5 d. At the end of the period, necrosis and varying degrees of erythema with diffuse areas of eschar and bleeding were noted. Data from published literature suggested that the test substance was corrosive to rabbit skin (BIBRA, 1989; CIR, 1989).

Also, the Biocides assessment report on C12-16 ADBAC, concluded that the test substance to be corrosive to the skin (ECHA biocides assessment report, 2015).

Therefore, based on the available information and in line with the biocides assessment report, the test substance is concluded to be corrosive to the skin.  

Eye

Study 1:A study was conducted to determine the eye irritation/corrosion potential of the test substance, C12-16 ADBAC (80% active in water) according to a method similar to OECD Guideline 405. The experiment was performed on rabbits. All six test rabbits received 0.1 mL of the undiluted test substance in one eye. The other eye remained untreated. Eyes were not washed throughout the study. After 24, 48 and 72 h, eyes were evaluated for ocular lesions according to the Draize scale. Under the conditions of the study, the test substance produced severe and irreversible damage in rabbit eyes (Wallace, 1975).

Study 2:A study was conducted to determine the eye irritation/corrosion potential of the test substance, C12-16 ADBAC (purity not specified) according to a method similar to OECD Guideline 405. The experiment was performed on New Zealand rabbits. A single application of the undiluted test substance to the eye of 6 rabbits produced severe corneal opacity, iritis, and moderate erythema and chemosis. There was a delayed occurrence of the effects, therefore, the mean values on Days 5 -7 were chosen for the evaluation. Under the study conditions, the test substance produced serious eye damage to rabbits (Sterner, 1981).

Study 3:A study was conducted to determine the eye irritation/corrosion potential of the test substance (purity not specified) according to a method similar to OECD Guideline 405. The experiment was performed on albino rabbits. A single application of the undiluted test substance to the non-irrigated eye of 6 rabbits produced severe corneal opacity, conjunctivitis and blanching of the conjunctival membranes. Iritis could not be scored due to the severe corneal opacity. Crystallization and fissuring were noted in one or two animals. The animals were observed for 3 days after application. Under the study conditions, the undiluted test substance produced serious eye damage to rabbits (Anspach, 1976).

Study 4:A study was conducted to determine the eye irritation/corrosion potential of the test substance, C12-16 ADBAC (0.1% active in water) according to a method similar to OECD Guideline 405. The experiment was performed on albino rabbits. A single application of the test substance as a 0.1% aqueous solution to the non-irrigated eye of nine rabbits produced moderate effects on the conjunctivae 1 h after application, but these had disappeared within 1 day. The animals were observed for 7 days after application. Under the study conditions, the test substance as a 0.1% aqueous solution was not irritating to the rabbit eye (Hixson, 1968).

As per CIR (1989) concentrations above 1% and higher caused severe damage of the rabbit eye upon twice daily instillation for 7 d (CIR, 1989).

The Biocides assessment report on C12-16 ADBAC, concluded the test substance to be corrosive to the eye (ECHA biocides assessment report, 2015).

Overall, based on the available information and in line with the biocides assessment report, the test substance is concluded to be corrosive to the eye.  

Based on the results of the in vivo skin and eye irritation studies, the test substance warrants a ‘Skin Corr. 1B; H314: Causes severe skin burns and eye damage’ as well as serious eye damage, ‘Eye dam. 1; H31: Causes serious eye damage’ classification according to the EU CLP criteria (Regulation EC 1272/2008). Labelling for the eye irritation endpoint is covered by the above classifications for skin effects.

With regard to respiratory tract irritation, although the test substance is very corrosive, its low vapour pressure prohibits the occurrence of respiratory irritation by vapour. Further, the classification of corrosive is already considered to implicitly cover the potential of RTI; therefore, an additional Cat.3 is considered to be superfluous (Guidance CLP Ch. 3.8.2.5).

Reason / purpose for cross-reference:
data waiving: supporting information
Reference

Based on the results of the read across studies with C12-16 ADBAC, no toxicologically significant systemic toxicity is expected for the test substance. In line with the biocides assessment report, it was concluded that all effects could be attributed to local gastrointestinal irritation/corrosion and consequently reduced food intake without observing any primary systemic effect. Therefore, selection of critical NOAEL and the derivation of a systemic NOAEL or DNEL was deemed inappropriate  

Toxic effect type:
concentration-driven
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
45 mg/kg bw/day
Study duration:
subchronic
Experimental exposure time per week (hours/week):
168
Species:
dog
Quality of whole database:
The information requirement for this tonnage band is sufficiently met with the available data.

System:
other: no true systemic effects
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available

Oral:

Study 1:

Dose range-finding: A 14-day range-finding study was conducted to determine the dose levels for a 90-day repeated dose oral toxicity of the read across substance, C12-16 ADBAC (48.9% active) in Sprague-Dawley rats, according to OECD Guideline 407, in compliance with GLP. In this study, the read across substance was administered to six rats per sex per group at dietary doses of 0, 1250, 2500 and 5000 ppm i.e., equivalent to 0, 650, 1250 and 2500 ppm a.i. or 0, 112, 229 or 436 mg/kg bw/d for males and 0, 116, 229 or 427 mg/kg bw/d for females. Besides lower food intake with related lower increase of body weight gain in all groups, which was due to the palatability of the read across substance, no toxic effects were observed. Under the study conditions, the NOAEL for systemic toxicity was > 2500 ppm (i.e., equivalent to 436 and 427 mg/kg bw/day or 218 and 214 mg a.i./kg bw/d for males and females, respectively) (Chevalier, 2002).

Main study: A 90-day study was conducted to determine the repeated dose oral toxicity of the read across substance, C12-16 ADBAC (48.9% active in water) in Sprague-Dawley rats according to OECD Guideline 409, in compliance with GLP. In this study, the read across substance was administered to ten rats per sex per group, at dietary doses of 0, 400, 1000 and 2500 ppm (equivalent to 0, 28, 68 and 166 mg a.i./kg bw/day for the males and 0, 30, 74 and 188 mg a.i./kg bw/day for the females, based on food consumption and body weight information). No signs indicative of toxicity was observed in any group. At 2500 ppm, the only effect was a decrease in body weight gain (statistically significant) correlating with lower food consumption due to the low palatability of the read across substance. Further, some statistically significant deviation from control in haematological and clinical-chemistry values were observed. However, in the absence of a dose-response relation, these effects were considered to be of no clinical significance. Under the conditions of the study, the rat NOEL for systemic effects was established at 1000 ppm (i.e., equivalent to 68 and 74 mg a.i./kg bw/day for males and females, respectively) (Chevalier, 2002).

 

Study 2: A 90 d study was conducted to determine the repeated dose oral toxicity of the read across substance, C12-16 ADBAC (79.7 -80.5% active) in Sprague Dawley rats, according to OECD Guideline 408 and US EPA OPP 82 -1, in compliance with GLP. In this study, the rats were administered daily dietary levels of 0, 100, 500, 1000, 4000 and 8000 ppm read across substance, equivalent to 0, 6, 31 and 62 mg/kg bw/day (i.e. 0, 4.8, 25 and 50 mg a.i./kg bw/day) (males) and 0, 8, 38 and 77 mg/kg bw/day (i.e. 0, 6.4, 30 and 62 mg a.i./kg bw/day) (females) for 95 and 96 days, respectively. Daily intakes at 4000 and 8000 ppm could not be calculated due to high mortality. The animals were observed for mortality, clinical signs, body weight, food consumption, hematology and clinical chemistry at termination. Gross and histopathological examinations were also performed. Other than a slight trend in reduced body weight and food consumption in males at 1000 ppm, there were no treatment-related findings at 1000 ppm or less. The highest dose of the read across substance led to 100 and 80% mortality for 8000 and 4000 ppm group respectively indicating 1000 ppm to be the maximal tolerated dose. The animals that survived at 4000 ppm were cachectic and debilitated. The probable cause of death was assumed to be shock secondary to fluid and/or ionic shifts in the gastro-intestinal tract, which was attributed to irritation and corrosivity properties of the substance. The females showed less aberrations in all measurements than the males. Based on the decreased food consumption and body weights at 1000 ppm, the NOEL for the read across substance was established at 500 ppm in the diet, i.e., equivalent to 31 mg/kg bw/day (i.e., 25 mg a.i./kg bw/day) for males and 38 mg/kg bw/day (i.e., 30 mg a.i./kg bw/day) for females (Van Miller, 1988).

Study 3:

Dose range-finding: A 14-day range finding study was conducted to determine the dose levels for a 28-day repeated dose oral toxicity of the read across substance, C12 -16 ADBAC (purity 49.9%) in Beagle dogs, according to OECD Guideline 407. In Phase I, four incremental doses of 500, 1000, 2000 and 5000 ppm were administered to 4 animals (2 males and 2 females). At 500 and 1000 ppm, no overt signs of toxicity were noted. At 2000 ppm, a moderate to marked decrease in body weight and food consumption was seen in the male. At 5000 ppm, a slight to moderate decrease in body weight and food consumption was observed in the male and female. No treatment-related laboratory or histopathological changes were noted. Taking into consideration these findings, one male and one female were then treated daily with the read across substance at 2000 ppm (i.e., equivalent to 43 and 53 mg/kg bw/day (21.5 and 26.4 mg a.i./kg bw/day) in males and females respectively) for 2 weeks (Phase II). Under the study conditions, reduced food consumption was recorded throughout the treatment period. A slight decrease in protein, albumin and triglyceride levels and alkaline phosphatase activity was noted as well. Consequently, the dose levels of 250, 500 and 1000 ppm of active read across substance were chosen for the 28-day repeated dose toxicity study in beagle dogs (Gaou, 2004).

Main study: A 28-day study was conducted to determine the repeated dose oral toxicity of the read across substance, C12 -16 ADBAC (purity 49.9%) in Beagle dogs, according to OECD Guideline 409, in compliance with GLP. In this study, the read across substance was administered to 2 dogs per sex per group, at dietary doses of 0, 500, 1000 and 2000 ppm, corresponding to approximately 0, 250, 500 and 1000 ppm a.i., respectively. The homogeneity and stability of the read across substance under the administration conditions was checked before treatment start. Concentrations were measured in each dietary admixture in Week 1 and 4. No treatment-related effects were observed up to the highest tested dose. Under the conditions of the study, the 28-day NOEL for systemic effects in Beagle dogs was established at the highest tested dose of 1000 ppm a.i. (i.e., equivalent to a mean actual dose of 36.70 mg a.i./kg bw/day) (Gaou, 2006).

Study 4: A 90-day study was conducted to determine the repeated dose oral toxicity of the read across substance, C12-16 ADBAC (49.6% active in water) in Beagle dogs according to OECD Guideline 409, in compliance with GLP. The read across substance was administered to four animals per sex per dose group at dietary doses of 0, 500, 1500 and 3000 ppm (i.e., equivalent to 0, 250, 750 or 1500 ppm a.i.). From Week 8, the concentration of read across substance was reduced to 2500 ppm (i.e., 1250 ppm a.i.) in the high dose female group due to low food intake and reduced body weight among these animals (up to 20%). The mean achieved dosage of active substance, based on food consumption and body weight, were 0, 8, 25 and 50 mg a.i./kg bw/day for males and 0, 9, 26 and 45 mg a.i./kg bw/day for females. One out of 4 female dogs in the high dose group (1500 ppm a.i.) showed emaciated appearance and soft faeces. No other clinical signs were attributed to treatment with the read across substance.Themean body weight gain were recorded to be similar to the control females following reduction of the high dose group to 1250 ppm a.i. Consequently, the prior effects on body weights at 1500 ppm a.i. were considered to be due to reduced palatability. Also, slightly lower clinical chemistry parameters (i.e., mean protein and cholesterol levels) were noted in females from the high-dose group when given 1500 ppm a.i., consistently with the decrease of food intake. These differences were no longer observed at the end of the treatment period and after dose reduction to 1250 ppm a.i. Under the study conditions, the 90-d NOAEL for systemic effects in Beagle dogs was established at the highest adjusted test dose of 1250 ppm (i.e., equivalent 45 mg a.i./kg bw/day, respectively) (Guillaumat, 2006).

Chronic toxicity studies:

Study 1: A study was conducted to determine the repeated dose oral toxicity study of the read across substance, C12 -16 ADBAC (49.2 - 49.9% active in water) according to OECD Guideline 453, in compliance with GLP. This experiment evaluated the chronic toxicity and carcinogenic potential of the test substance in a combined study. The read across substance was administered daily to Sprague-Dawley rats by dietary admixture at the concentrations of 1000, 2000 and 4000 ppm (equivalent to 500, 1000 and 2000 ppm a.i.) for 52 weeks (toxicology sub-group) (equivalent to 28, 56 or 109 mg a.i./kg bw/d for males and to 33, 65 or 133 mg a.i./kg bw/d for females, respectively) and for 104 weeks (carcinogenicity sub-group) (corresponding to 24, 48 or 97 mg a.i./kg bw/d for males and 29, 58 or 119 mg a.i./kg bw/d for females). The read across substance did not induce any treatment-related mortality or clinical signs when administered daily for 52 or 104 weeks. At 4000 ppm, the mean body weight and body weight gain of the males of the toxicology sub-group and of the males and females of the carcinogenicity sub-group were lower than that of the controls, correlating with slightly lower mean food consumption. There were no significant differences in haematological, biochemical and/or urinalysis parameters at any dose-level for animals of either sub-group, compared with controls. There were no macroscopic or microscopic findings attributable to the read across substance at any dose levels. Under the study conditions, due to the observed lower body weight gain at 4000 ppm substance (significant only in males of 52-week chronic study part; significant in males and females in 104-week carcinogenicity group), the NOEL was established at 2000 ppm (equivalent to 56 and 65 mg a.i./kg bw/d for males and females for chronic groups or 48 and 58 mg a.i./kg bw/d in males and females for carcinogenicity groups) (Appelqvist, 2007).

Study 2: A study was conducted to determine the repeated dose oral toxicity of the read across substance (81.09% in aqueous/ethanol solution) according to OECD Guideline 453 and US EPA OPPTS 870.4300, in compliance with GLP. This two-year combined dietary toxicity and carcinogenicity study was conducted in Sprague-Dawley CD rats. The read across substance was administered rats (60/sex/group) at dose levels of 0, 300, 1000 or 2000 ppm read across substance (equivalent to mean intake levels of 0, 13, 44, and 88 mg/kg bw/d in males and 0, 17, 57 and 116 mg/kg bw/d in females) in the diet daily for 104 weeks. There were two control groups of 60/sex/group each. The animals were observed twice daily and body weights and clinical findings were recorded periodically. Clinical pathology measurements (haematology, clinical chemistry and urinalysis) were made at 6, 12, 18 and 24 months. At termination, a thorough post-mortem examination was conducted on all animals. Histopathology was conducted on a full set of tissues and organs from all animals in the control and high dose groups as well as on selected organs from animals in the low and mid-dose groups. An increased incidence of loose faeces in male rats was observed which was considered to be potentially treatment-related, however, was not of biological significance. A reduction in mean absolute bodyweights and food consumption was observed in males and females in the high dose group. No other treatment related effects were observed for clinical pathology, organ weights, gross and histopathology or ophthalmology. Based on the results of the study, the NOAEL for chronic toxicity was determined to be 1000 ppm in diet (44 mg/kg bw/d for males and 57 mg/kg bw/d for females, equivalent to 35.64 and 46.17 mg a.i./kg bw/d respectively) (Gill, 1991).

As per the Biocides assessment report on C12-16 ADBAC, which was published by the Italian authorities in June 2015, reported the above studies and stated that “the effects on which the NOEL derivation could have been based, independently on the species tested, was the reduction in body weight and body weight gain, consistent with decreased food consumption (US ISC; EQC). It was concluded that all effects could be attributed to local gastrointestinal irritaton/corrosion and consequent reduced food intake without observing any primary systemic effect. Therefore, the derivation of a NOAEL for systemic effects was deemed inappropriate."

Therefore, in line with the biocides assessment report and given that the read across to C12-16 ADBAC can be justified for the test substance based on a category approach, derivation of systemic NOAEL andDNEL has been considered to be non-relevant and only a qualitative local risk assessment has been conducted for the test substance. 

Inhalation:

The substance is considered to have a low vapour pressure (VP = 0.0058 Pa at 25°C, based on read across), which is below the cut-off of 0.01 Pa set for defining low volatility substances, as per the ECHA Guidance R.7a. Therefore, due to its solid physical state and low VP, the test substance is unlikely that it will form inhalable dust, mist or fumes when handled and used in solid form. In case inhalable forms of the substance (either pure or in aqueous solutions) are created under particular conditions (e.g., spraying, elevated temperature/pressure), appropriate risk management measures (due to corrosive nature of the test substance) such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Under such conditions, the risk to humans following inhalation exposure can be considered minimal and further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation. Nevertheless, a qualitative risk assessment has been carried out for this route, due to the corrosive nature of the test substance and the fact that the available repeated dose oral studies with the read across substance did not show any primary systemic effects; all observed effects were attributed to local gastrointestinal irritation/corrosion and consequent reduced food intake.

Dermal:

A repeated dose dermal toxicity study for the test substance is not required because the endpoint can be assessed based on the available sub-chronic oral studies with the read across substance, C12-16 ADBAC, which indicated that the main critical effects were due to the corrosive properties of the substance. Further, given the corrosive nature of the test substance together with the fact that the toxicokinetic assessment did not indicate higher absorption potential for the dermal route, any further testing on animals may be omitted due to animal welfare reasons, in accordance with Annex XI (1.2) of the REACH regulation. Nevertheless, a qualitative risk assessment has been carried out for this route, due to the corrosive nature of the test substance.

Based on the observed effects and the available NOAELs and LOAELs from the repeated dose studies, the test substance does not warrant a classification for STOT RE according to the EU CLP criteria (Regulation 1272/2008/EC).  

Data source

Materials and methods

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion