Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
An assessment of toxicokinetics, based on available data, in accordance with Annex VIII, Section 8.8.1 of Regulation (EC) No 1907/2006
Type of information:
other: Desk-based assessment
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Objective of study:
toxicokinetics
Principles of method if other than guideline:
An assessment of toxicokinetics, based on available data, in accordance with Annex VIII, Section 8.8.1 of Regulation (EC) No 1907/2006
GLP compliance:
no
Specific details on test material used for the study:
Detailed information on the 'test material identity' is provided in the attached document including information on individual constituents.
Details on species / strain selection:
No animals were used in this desk-based assessment.
Details on test animals or test system and environmental conditions:
Not applicable
Details on exposure:
Desk-based assessment.
Duration and frequency of treatment / exposure:
Desk-based assessment.
No. of animals per sex per dose / concentration:
No animals were used in this desk-based assessment.
Positive control reference chemical:
Desk-based assessment.
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable
Preliminary studies:
Desk-based assessment.
Details on absorption:
The substance has a molecular weight range of ca. 97 to ca. 434 g/mol, an n-octanol/water log Kow range: ca. -2.00 to 2.80 at pH 7 and 35°C and/or ca. -0.8 to 2.8 at pH 2 and 35°C. No constituents are expected to have a log Pow > 3.0 at pH 4, pH 7 or pH 9 at 25°C (or ambient temperatures). The substance possesses a water solubility (range): 24.73 to 539000 mg/L in three blocks, at 25 °C; ca. pH 7, from QSAR Predictions. Essentially, the substance consists of constituents in the slightly soluble (1 – 100 mg/L) to soluble (> 1000 mg/L) range. The mass %wt majority of substances are in the ‘soluble (> 1000 mg/L)’ band. The substance vapour pressure was: < 7.6 Pa at 20 °C and < 12 Pa at 25 °C. These values (7.6 Pa at Pa at 20 °C and 12 Pa at 25 °C) are considered ‘limit values” for the substance for chemical assessment purposes. The substance is not considered to be surface active based on structural assessment.
For absorption by the dermal route: the physical chemical parameters including molecular weight, vapour pressure, water solubility and n-octanol/water partition coefficients (log Kow) of all constituents indicate favourable absorption via the dermal route. The substance is a liquid, meaning it is likely to be more favourably taken up by the skin than dry particulates (ECHA R.7c, 2017). The vapour pressure of the substance is lower than 0.76-76 mm Hg (and/or 101.325 to 10132.5 Pa) at 25°C, therefore the rate of evaporation from the skin is expected to be relatively low and this means that the substance is likely to be well absorbed through the stratum corneum (ECHA R.7c, 2017). The molecular weights of constituents vary from 97 – 434 g/mol. Dermal absorption is considered to be possible for molecules < 500 g/mol, with the optimal molecular weight being < 100 g/mol (ECHA R.7c, 2017). As all 9 constituents are < 500 g/mol it can be considered that molecular size is not prohibitive to absorption. However, it should be noted that only ca. 5% of the constituents are < 100 g/mol in size, therefore absorption may not be expected to be optimal based on this data alone. In addition, as molecular size is inversely proportional to lag time (time from substance contacting skin surface to being detected on the other side of the skin), it may be predicted that those constituents with a larger molecular weight could slow the overall penetration speed of the substance, in turn potentially reducing the overall dermal absorption for shorter exposure periods (scientific reference citation, given in the report). The optimal log Kow for dermal absorption is in the range of 1-4 (ECHA R.7c, 2017). The log Kow values of the constituents vary between -1.0 and 4.0. However, for 80% of these, the log Kow is < 1.0, indicating that absorption may be sub-optimal. dermal absorption is favourable as the water solubility of the majority of constituents also is high: ca. 70 % of the composition has a water solubility > 10,000 mg/L, and ca. 96 % has water solubility > 1000 mg/L. The average log Kow and water solubility values of constituents 1 to 9, fall within the dermal absorption criteria outlined above; therefore the dermal absorption is expected to be high (ECHA R.7c, 2017). As no direct data on absorption is available, a conservative ‘worst case’ approach must be taken in the assessment. Based on the evidence presented and according to ECHA’s guidance notes on dermal absorption (No. 156), a default value of 100 % skin absorption should be assumed (ECHA, 2019). In this assessment of the absorption capability of the substance is considered in its entirety and not as individual constituents.
For absorption by the gastro-intestinal (GI) tract: the water solubility (> 1000 mg/L; ca. 96% of constituents) lends the substance towards ease of dissolution in gastrointestinal fluid, and as the molecular weight the constituents is < 500 g/mol, the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water (ECHA R.7c, 2017). According to the scientific literature (citation, given in the report) the optimal log Kow for oral absorption falls within a range of 2-7. As the Log Kow for ca. 80% constituents is < 1.0 indicating the test substance is on the whole hydrophilic, this property alone indicates that absorption via the oral route is likely, but may be sub-optimal given it is a little out with the established ideal Log Kow range. However, as the substance is classified as corrosive, gastrointestinal absorption following oral exposure is likely to be significantly increased with enhanced membrane penetration due to increased permeability of the gastrointestinal tract (GIT). This may in turn increase the systemic bioavailability of the substance. Results of the combined repeated dose and screening for reproductive and developmental toxicity study on a read-across source substance noted systemic toxicity following exposure, indicating that absorption from the GIT indeed occurs (Anon., 2016). Furthermore, in two females found dead during the study period, discolouration & dark red foci in the stomach were reported following pathological examination. This indicates that the test substance is both corrosive to and absorbed from the GIT, as this finding was not reported in the control group. Use of corn oil as vehicle in this study may have contributed to absorption, as compounds delivered in oils that can be emulsified and digested are likely to be absorbed to a greater degree than those delivered in non-digestible mineral oil (scientific reference citation, given in the report). Based on the physical chemical properties and supporting evidence from oral toxicity data in the source substance, successful absorption from the GIT via passive diffusion is likely. Moreover, the test item is classified as corrosive which may damage the GIT membrane and further aid absorption, resulting in increased systemic bioavailability. Based on the above evidence and according to the relevant guidance (ECHA R.7a, 2017), a default value of 100 % gastrointestinal absorption is assumed. In this assessment of the absorption capability of the substance it is considered in its entirety and not as individual constituents.
For absorption by the respiratory tract: limited information is available on the vapour pressures of the individual constituents of the test substance. Data in the public domain is available solely on Phosphoric acid (constituent 1) and 2-hydroxyethyl methacrylate (constituent 3), which have vapour pressures of 0.03 mm Hg and up to 0.13 mm Hg (or 3.99 Pa and/or up to 17.3 Pa) at 20˚C, respectively. Following the OECD TG 104 study, the vapour pressure of the entire test substance was evaluated and determined to be < 7.6 Pa (0.06 mm Hg) at 20˚C and/or < 12 Pa (0.09 mm Hg) at 25˚C. Together, the vapour pressure and moderate log Kow values (-1.0 to 4.0) indicate the potential exists for inhalation of the substance, and subsequent absorption via the respiratory tract epithelium (ECHA R.7c, 2017). As the substance is water soluble, enhanced penetration to the lower respiratory tract may be expected. Absorption may occur via aqueous pores in the alveoli or remain retained in the mucous (likelihood of which is increased by its hydrophilic nature) before being transported out of the respiratory tract into the circulatory system (or transported out of the deposition region with the mucus and swallowed). Since respiratory exposure avoids first pass metabolism in the liver, a higher plasma concentration of the substance as well as plasma half-life may be expected. Based on the above evidence and according to the relevant guidance (ECHA R.7a, 2017), a default value of 100 % respiratory absorption is assumed. In this assessment of the absorption capability of the substance it is considered in its entirety and not as individual constituents.
Based on the evidence available at the current time, the following values should be assumed in relation to ADME of the substance:
Absorption (dermal) – 100%
Absorption (oral) – 100%
Absorption (respiratory) – 100%
Details on distribution in tissues:
The substance physico-chemical properties and evidence from a repeated dose study on a read-across source substance indicate: that the present (target) substance is likely to be absorbed and thus become systemically available. The substance has high water solubility (> 1000 mg/L; ca. 96 % of composition) and log Kow range (-2.0 to 2.8) which indicates that it is hydrophilic. As such it may be considered to have high plasma half-life, and with this an increased likelihood of systemic distribution and limited distribution into fatty tissues (ECHA R.7c, 2017). As the substance is corrosive (Category 1A) increased the systemic bioavailability may be expected due to enhanced GIT permeability. A combined repeated dose and screening for reproductive and developmental toxicity study on the read-across source substance identified several organs and tissues in which pathological observations were present, indicating systemic distribution within the rat. Highly lipophilic substances with a log Kow > 4.0 tend to have a longer half-life with the potential for accumulation also increasing (ECHA R.7a, 2017). As the log Kow values of all constituents are < 4.0, its (bio)accumulative potential is expected to be low. In support of this, no site-specific accumulation was noted in the read-across source substance OECD TG 422 study.
Details on excretion:
All nine constituents are of low to mid molecular weights and the substance itself has high water solubility (> 1000 mg/L; ca. 96 % of composition), making it highly likely be excreted via urine (ECHA R.7c, 2017). Any unabsorbed constituents are expected to be eliminated via faeces. This is supported by results of a combined repeated dose and screening for reproductive and developmental toxicity study on a read-across source substance which indicated: an increase in kidney weight in both males and females following exposure to 1000 mg/kg bw/day. No changes were noted following histopathological evaluation and no significant changes were noted in the blood chemistry, therefore it was concluded that the increase in kidney weight was an adaptive response, indicative of clearance of the test substance. Based on the absorption, distribution and potential metabolic pathways highlighted coupled with toxicological data available on the read-across substance: the test substance is most likely to be excreted via urine and faeces. This is supported by the high water solubility (> 1000 mg/L; ca. 96 % of composition) and the constituent log Kow range (-2.0 to 2.8). The present (target) substance is expected to be extensively excreted via urine (both itself and/or via conjugates).
Metabolites identified:
not measured
Details on metabolites:
It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone, and even more difficult to predict the extent to which it will be metabolised along different pathways and what species differences may exist (ECHA R.7c, 2017). However, basic inferences may be made based on the available data. As the substance is both hydrophilic and corrosive, following oral exposure paracellular absorption and absorption from the gut into portal vein is favoured and therefore first pass metabolism, ensuring rapid biotransformation and elimination. Metabolism is also likely to occur in the kidney before excretion in urine. Supportive evidence is provided from the results of an OECD TG 422 study on a read-across source substance, where evidence of local irritation was present in the GIT following oral exposure, and with adaptive increases in liver and kidney weights were observed at 1000 mg/kg bw/day alongside the presence of centrilobular hepatocellular hypertrophy in the liver. This is suggestive of metabolism in both liver and kidney.
Conclusions:
The substance possesses physicochemical properties which are favourable for ADME. The substance has a molecular weight range of ca. 97 to ca. 434 g/mol, an n-octanol/water log Pow range: ca. -2.00 to 2.80 at pH 7 and 35°C and/or ca. -0.8 to 2.8 at pH 2 and 35°C. No constituents are expected to have a log Kow > 3.0 at pH 4, pH 7 or pH 9 at 25°C (or ambient temperatures). The substance possesses a water solubility (range): 24.73 to 539000 mg/L in three blocks, at 25 °C; ca. pH 7, from QSAR Predictions. Essentially, the substance consists of constituents in the slightly soluble (1 – 100 mg/L) to soluble (> 1000 mg/L) range. The mass %wt majority of substances are in the ‘soluble (> 1000 mg/L)’ band. The substance vapour pressure was: < 7.6 Pa at 20 °C and < 12 Pa at 25 °C. These values (7.6 Pa at Pa at 20 °C and 12 Pa at 25 °C) are considered ‘limit values” for the substance for chemical assessment purposes. For absorption by the gastro-intestinal (GI) tract: a default value of 100 % gastrointestinal absorption is assumed. For absorption by the dermal route: the physical chemical parameters including molecular weight, vapour pressure, water solubility and n-octanol/water partition coefficients (log Kow) of all constituents indicate favourable absorption via the dermal route. A default value of 100 % dermal absorption is assumed. For absorption by the respiratory tract: a default value of 100 % respiratory absorption is assumed. The substance physico-chemical properties and evidence from a repeated dose study on a read-across source substance indicate: that the present (target) substance is likely to be absorbed and thus become systemically available. The substance has high water solubility (> 1000 mg/L; ca. 96 % of composition) and log Kow range (-2.0 to 2.8) which indicates that it is hydrophilic. As such it may be considered to have high plasma half-life, and with this an increased likelihood of systemic distribution and limited distribution into fatty tissues. As the substance is corrosive (Category 1A) increased the systemic bioavailability may be expected due to enhanced GIT permeability. As the substance is both hydrophilic and corrosive, following oral exposure paracellular absorption and absorption from the gut into portal vein is favoured and therefore first pass metabolism, ensuring rapid biotransformation and elimination. Metabolism is also likely to occur in the kidney before excretion in urine. Supportive evidence is provided from the results of an OECD TG 422 study on a read-across source substance, where evidence of local irritation was present in the GIT following oral exposure, and with adaptive increases in liver and kidney weights were observed at 1000 mg/kg bw/day alongside the presence of centrilobular hepatocellular hypertrophy in the liver. This is suggestive of metabolism in both liver and kidney. All nine constituents are of low to mid molecular weights and the substance itself has high water solubility (> 1000 mg/L; ca. 96 % of composition), making it highly likely be excreted via urine. Any unabsorbed constituents are expected to be eliminated via faeces. The present substance is expected to be extensively excreted via urine (both itself and/or via conjugates). Through evaluation of the available data on the substance, it is concluded the data is demonstrative of distribution, biotransformation and elimination of the substance. The substance is predicted not to be (bio)accumulative.
Executive summary:

A desk-based assessment of the basic toxicokinetics of the substance, in accordance with Regulation (EC) 1907/2006: Annex VIII - Section 8.8.1. The substance possesses physicochemical properties which are favourable for ADME. The substance has a molecular weight range of ca. 97 to ca. 434 g/mol, an n-octanol/water log Pow range: ca. -2.00 to 2.80 at pH 7 and 35°C and/or ca. -0.8 to 2.8 at pH 2 and 35°C. No constituents are expected to have a log Kow > 3.0 at pH 4, pH 7 or pH 9 at 25°C (or ambient temperatures). The substance possesses a water solubility (range): 24.73 to 539000 mg/L in three blocks, at 25 °C; ca. pH 7, from QSAR Predictions. Essentially, the substance consists of constituents in the slightly soluble (1 – 100 mg/L) to soluble (> 1000 mg/L) range. The mass %wt majority of substances are in the ‘soluble (> 1000 mg/L)’ band. The substancevapour pressure was:< 7.6 Pa at 20 °C and < 12 Pa at 25 °C. These values (7.6 Pa at Pa at 20 °C and 12 Pa at 25 °C) are considered ‘limit values” for the substance for chemical assessment purposes. The substance is not considered to be surface active based on structural assessment.For absorption by the gastro-intestinal (GI) tract: the water solubility (> 1000 mg/L; ca. 96% of constituents) lends the substance towards ease of dissolution in gastrointestinal fluid, and as the molecular weight the constituents is < 500 g/mol, the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. According to the scientific literature (citation, given in the report) the optimal log Kow for oral absorption falls within a range of 2-7. As the log Kow for ca. 80% constituents is < 1.0 indicating the test substance is on the whole hydrophilic, this property alone indicates that absorption via the oral route is likely, but may be sub-optimal given it is a little out with the established ideal log Kow range. However, as the substance is classified as corrosive, gastrointestinal absorption following oral exposure is likely to be significantly increased with enhanced membrane penetration due to increased permeability of the gastrointestinal tract (GIT). This may in turn increase the systemic bioavailability of the substance. Based on the physical chemical properties and supporting evidence from oral toxicity data in the source substance, successful absorption from the GIT via passive diffusion is likely. Moreover, the test item is classified as corrosive which may damage the GIT membrane and further aid absorption, resulting in increased systemic bioavailability. Based on the above evidence and according to the relevant guidance, a default value of 100 % gastrointestinal absorption is assumed. For absorption by the dermal route: the physical chemical parameters including molecular weight, vapour pressure, water solubility and n-octanol/water partition coefficients (log Kow) of all constituents indicate favourable absorption via the dermal route.A default value of 100 % dermal absorption is assumed.For absorption by the respiratory tract: limited information is available on the vapour pressures of the individual constituents of the test substance. Data in the public domain is available solely on Phosphoric acid (constituent 1) and 2-hydroxyethyl methacrylate (constituent 3), which have vapour pressures of 0.03 mm Hg and up to 0.13 mm Hg (or 3.99 Pa and/or up to 17.3 Pa) at 20˚C, respectively. The vapour pressure of the entire test substance was evaluated and determined to be < 7.6 Pa (0.06 mm Hg) at 20˚C and/or < 12 Pa (0.09 mm Hg) at 25˚C. Together, the vapour pressure and moderate log Kow values (-1.0 to 4.0) indicate the potential exists for inhalation of the substance, and subsequent absorption via the respiratory tract epithelium. As the substance is water soluble, enhanced penetration to the lower respiratory tract may be expected. Absorption may occur via aqueous pores in the alveoli or remain retained in the mucous (likelihood of which is increased by its hydrophilic nature) before being transported out of the respiratory tract into the circulatory system (or transported out of the deposition region with the mucus and swallowed). Since respiratory exposure avoids first pass metabolism in the liver, a higher plasma concentration of the substance as well as plasma half-life may be expected. A default value of 100 % respiratory absorption is assumed. The substance physico-chemical properties and evidence from a repeated dose study on a read-across source substance indicate: that the present (target) substance is likely to be absorbed and thus become systemically available. The substance has high water solubility (> 1000 mg/L; ca. 96 % of composition) and log Kow range (-2.0 to 2.8) which indicates that it is hydrophilic. As such it may be considered to have high plasma half-life, and with this an increased likelihood of systemic distribution and limited distribution into fatty tissues. As the substance is corrosive (Category 1A) increased the systemic bioavailability may be expected due to enhanced GIT permeability. A combined repeated dose and screening for reproductive and developmental toxicity study on the read-across source substance identified several organs and tissues in which pathological observations were present, indicating systemic distribution within the rat. As the log Kow values of all constituents are < 4.0, its (bio)accumulative potential is expected to be low. In support of this, no site-specific accumulation was noted in the read-across source substance OECD TG 422 study. It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone, and even more difficult to predict the extent to which it will be metabolised along different pathways and what species differences may exist. However, basic inferences may be made. As the substance is both hydrophilic and corrosive, following oral exposure paracellular absorption and absorption from the gut into portal vein is favoured and therefore first pass metabolism, ensuring rapid biotransformation and elimination. Metabolism is also likely to occur in the kidney before excretion in urine. Supportive evidence is provided from the results of an OECD TG 422 study on a read-across source substance, where evidence of local irritation was present in the GIT following oral exposure, and with adaptive increases in liver and kidney weights were observed at 1000 mg/kg bw/day alongside the presence of centrilobular hepatocellular hypertrophy in the liver. This is suggestive of metabolism in both liver and kidney. All nine constituents are of low to mid molecular weights and the substance itself has high water solubility (> 1000 mg/L; ca. 96 % of composition), making it highly likely be excreted via urine. Any unabsorbed constituents are expected to be eliminated via faeces. This is supported by results of a combined repeated dose and screening for reproductive and developmental toxicity study on a read-across source substance which indicated: an increase in kidney weight in both males and females following exposure to 1000 mg/kg bw/day. No changes were noted following histopathological evaluation and no significant changes were noted in the blood chemistry, therefore it was concluded that the increase in kidney weight was an adaptive response, indicative of clearance of the test substance. Based on the absorption, distribution and potential metabolic pathways highlighted coupled with toxicological data available on the read-across substance: the test substance is most likely to be excreted via urine and faeces. This is supported by the high water solubility (> 1000 mg/L; ca. 96 % of composition) and the constituent log Kow range (-2.0 to 2.8). The present (target) substance is expected to be extensively excreted via urine (both itself and/or via conjugates). Through evaluation of the available data on the substance, it is concluded the data is demonstrative of distribution, biotransformation and elimination of the substance. The substance is predicted not to be (bio)accumulative.

Description of key information

Toxicokinetics Assessment: no bioaccumulation potential; desk-based assessment in accordance with Regulation (EC) 1907/2006: Annex VIII, Section 8.8.1, 2021

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

Basictoxicokinetics (expert assessment, 2021): A desk-based assessment of the basic toxicokinetics of the substance, in accordance with Regulation (EC) 1907/2006: Annex VIII - Section 8.8.1. The substance possesses physicochemical properties which are favourable for ADME. The substance has a molecular weight range of ca. 97 to ca. 434 g/mol, an n-octanol/water log Kow range: ca. -2.00 to 2.80 at pH 7 and 35°C and/or ca. -0.8 to 2.8 at pH 2 and 35°C. No constituents are expected to have a log Kow > 3.0 at pH 4, pH 7 or pH 9 at 25°C (or ambient temperatures). The substance possesses a water solubility (range): 24.73 to 539000 mg/L in three blocks, at 25 °C; ca. pH 7, from QSAR Predictions. Essentially, the substance consists of constituents in the slightly soluble (1 – 100 mg/L) to soluble (> 1000 mg/L) range. The mass %wt majority of substances are in the ‘soluble (> 1000 mg/L)’ band. The substance vapour pressure was: < 7.6 Pa at 20 °C and < 12 Pa at 25 °C. These values (7.6 Pa at Pa at 20 °C and 12 Pa at 25 °C) are considered ‘limit values” for the substance for chemical assessment purposes. The substance is not considered to be surface active based on structural assessment. For absorption by the gastro-intestinal (GI) tract: the water solubility (> 1000 mg/L; ca. 96% of constituents) lends the substance towards ease of dissolution in gastrointestinal fluid, and as the molecular weight the constituents is < 500 g/mol, the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. According to the scientific literature (citation, given in the report) the optimal log Kow for oral absorption falls within a range of 2-7. As the Log Kow for ca. 80% constituents is < 1.0 indicating the test substance is on the whole hydrophilic, this property alone indicates that absorption via the oral route is likely, but may be sub-optimal given it is a little out with the established ideal Log Kow range. However, as the substance is classified as corrosive, gastrointestinal absorption following oral exposure is likely to be significantly increased with enhanced membrane penetration due to increased permeability of the gastrointestinal tract (GIT). This may in turn increase the systemic bioavailability of the substance. Based on the physical chemical properties and supporting evidence from oral toxicity data in the source substance, successful absorption from the GIT via passive diffusion is likely. Moreover, the test item is classified as corrosive which may damage the GIT membrane and further aid absorption, resulting in increased systemic bioavailability. Based on the above evidence and according to the relevant guidance, a default value of 100 % gastrointestinal absorption is assumed. For absorption by the dermal route: the physical chemical parameters including molecular weight, vapour pressure, water solubility and n-octanol/water partition coefficients (log Kow) of all constituents indicate favourable absorption via the dermal route. A default value of 100 % dermal absorption is assumed. For absorption by the respiratory tract: limited information is available on the vapour pressures of the individual constituents of the test substance. Data in the public domain is available solely on Phosphoric acid (constituent 1) and 2-hydroxyethyl methacrylate (constituent 3), which have vapour pressures of 0.03 mm Hg and up to 0.13 mm Hg (or 3.99 Pa and/or up to 17.3 Pa) at 20˚C, respectively. The vapour pressure of the entire test substance was evaluated and determined to be < 7.6 Pa (0.06 mm Hg) at 20˚C and/or < 12 Pa (0.09 mm Hg) at 25˚C. Together, the vapour pressure and moderate log Kow values (-1.0 to 4.0) indicate the potential exists for inhalation of the substance, and subsequent absorption via the respiratory tract epithelium. As the substance is water soluble, enhanced penetration to the lower respiratory tract may be expected. Absorption may occur via aqueous pores in the alveoli or remain retained in the mucous (likelihood of which is increased by its hydrophilic nature) before being transported out of the respiratory tract into the circulatory system (or transported out of the deposition region with the mucus and swallowed). Since respiratory exposure avoids first pass metabolism in the liver, a higher plasma concentration of the substance as well as plasma half-life may be expected. A default value of 100 % respiratory absorption is assumed. The substance physico-chemical properties and evidence from a repeated dose study on a read-across source substance indicate: that the present (target) substance is likely to be absorbed and thus become systemically available. The substance has high water solubility (> 1000 mg/L; ca. 96 % of composition) and log Kow range (-2.0 to 2.8) which indicates that it is hydrophilic. As such it may be considered to have high plasma half-life, and with this an increased likelihood of systemic distribution and limited distribution into fatty tissues. As the substance is corrosive (Category 1A) increased the systemic bioavailability may be expected due to enhanced GIT permeability. A combined repeated dose and screening for reproductive and developmental toxicity study on the read-across source substance identified several organs and tissues in which pathological observations were present, indicating systemic distribution within the rat. As the log Kow values of all constituents are < 4.0, its (bio)accumulative potential is expected to be low. In support of this, no site-specific accumulation was noted in the read-across source substance OECD TG 422 study. It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone, and even more difficult to predict the extent to which it will be metabolised along different pathways and what species differences may exist. However, basic inferences may be made. As the substance is both hydrophilic and corrosive, following oral exposure paracellular absorption and absorption from the gut into portal vein is favoured and therefore first pass metabolism, ensuring rapid biotransformation and elimination. Metabolism is also likely to occur in the kidney before excretion in urine. Supportive evidence is provided from the results of an OECD TG 422 study on a read-across source substance, where evidence of local irritation was present in the GIT following oral exposure, and with adaptive increases in liver and kidney weights were observed at 1000 mg/kg bw/day alongside the presence of centrilobular hepatocellular hypertrophy in the liver. This is suggestive of metabolism in both liver and kidney. All nine constituents are of low to mid molecular weights and the substance itself has high water solubility (> 1000 mg/L; ca. 96 % of composition), making it highly likely be excreted via urine. Any unabsorbed constituents are expected to be eliminated via faeces. This is supported by results of a combined repeated dose and screening for reproductive and developmental toxicity study on a read-across source substance which indicated: an increase in kidney weight in both males and females following exposure to 1000 mg/kg bw/day. No changes were noted following histopathological evaluation and no significant changes were noted in the blood chemistry, therefore it was concluded that the increase in kidney weight was an adaptive response, indicative of clearance of the test substance. Based on the absorption, distribution and potential metabolic pathways highlighted coupled with toxicological data available on the read-across substance: the test substance is most likely to be excreted via urine and faeces. This is supported by the high water solubility (> 1000 mg/L; ca. 96 % of composition) and the constituent log Kow range (-2.0 to 2.8). The present (target) substance is expected to be extensively excreted via urine (both itself and/or via conjugates). Through evaluation of the available data on the substance, it is concluded the data is demonstrative of distribution, biotransformation and elimination of the substance. The substance is predicted not to be (bio)accumulative.

 

The substance possesses physico-chemical properties which are favourable for ADME. Based on the log Kow of < 4.5 and BCF < 2,000, bioaccumulation is not significant and elimination is expected to be rapid.

 

References:

1. ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7c: Endpoint Specific Guidance, June 2017) 

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