Reaction products of dimethyl phosphonate with 2-alkyl-2-alkylpropanediol and alkanediol

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: expert opinion

Adequacy of study:

key study

Study period:

July 2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

The following assessment of the toxicokinetic profile of the registered substance is based on the physical chemical properties and toxicity data on the substance. No experimentally derived ADME data are available for this substance.

GLP compliance:

no

Type:

absorption

Results:

likely during dermal exposure

Type:

distribution

Results:

expected to be circulated via the blood to the liver and other tissues

Type:

metabolism

Results:

unlikely to be metabolically activated to toxic intermediates

Type:

excretion

Results:

expected to be excreted rapidly via the kidneys with non-absorbed material excreted via the feces

Details on absorption:

Dermal route
The dermal absorption of the main components of this substance is expected to be limited because the MW of even the smallest component is >100. However, the solubility in water and the lipid solubility indicate that dermal absorption of the substance is favored and may be enhanced by iif the paste becomes liquid. ECHA endpoint specific guidance chapter R.7C indicates that for substances with a MW <100 are favored for absorption and if water solubility is >10g/L and a Log PoW <0, then the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. This substance has physicochemical properties that mostly favor dermal absorption. Consequently, absorption via the dermal route is expected to be moderate, which is supported by the toxicity data; the substance is corrosive to skin. Furthermore, damage to the skin caused by its corrosive nature may further enhance dermal absorption. However, the dermal acute toxicity of the substance shows that the LD50 is greater than 2000 mg/kg, which may indicate that dermal absorption is low, or that the substance has low intrinsic toxicity. Based on the toxicological evidence, the test substance is likely to be absorbed following dermal application, however, because of its corrosive properties, dermal exposure is expected to be limited or controlled under normal use conditions.

Oral route
Absorption in the gastrointestinal tract is predominantly influenced by the water solubility, ionization state, lipophilicity, and molecular weight of a chemical. The substance is soluble in water and has a lipid solubility that is inside the LogPow range of -1 to 4 that is considered favorable for absorption. The MW covers a wide range, but a significant proportion of the substance has a MW below 500, which may permit passive absorption. Furthermore, the substance is hydrolyzed at the temperature and pH conditions of the intestine, which may further promote absorption. However, the substance components are ionizable, which is generally considered to inhibit absorption, depending on the pKa. The results of an acute oral toxicity study indicate no evidence of systemic toxic effects at 2000 mg/kg/bw, which may be because the substance has low absorption or because of low intrinsic toxicity. The results of repeated dose toxicity, reproductive toxicity, and developmental toxicity studies all indicate that the substance, or some components of the substance, are absorbed. In the 28-day repeated dose study there was evidence of effects in the male kidney (hyaline droplets). Whilst these effects were not adverse and reversible, they do indicate that there was absorption, systemic exposure, and excretion via the kidney. Local toxicity was observed as hyperplasia and hyperkeratosis in the non-glandular stomach. In a reproductive screening toxicity study, there were effects at the high dose level on post-natal survival, pup bodyweights and bodyweight gains. These effects were mirrored in a developmental toxicity study where there were reductions in fetal bodyweight at the high dose level. There were no histopathological correlates for these observations and no obvious toxicological mode of action. Furthermore, there were no toxicological effects on the parental animals except for lower food consumption by the females in the reproductive toxicity study, and the probable local toxicity/irritation to the non-glandular stomach. At face value, the effects on the offspring can be taken as evidence of absorption and systemic exposure.

Inhalation route
The substance is a paste at ambient temperature and has low vapor pressure, therefore the potential for inhalation exposure via vapor is considered to be highly unlikely.

Details on distribution in tissues:

Once this substance (or at least the absorbable components) is absorbed, it is expected to be circulated via the blood to the liver and other tissues. Due to its ionized nature it is predicted not to be significantly absorbed by the cells of the organs and tissues that it contacts except for the kidney. The substance is unlikely to bioaccumulate because of its generally low lipid solubility.

Details on excretion:

Because of the physicochemical characteristics of this substance any absorbed material is expected to be excreted rapidly via the kidneys and non-absorbed material will be excreted via the feces.

Metabolites identified:

no

Details on metabolites:

The absorbed components of this UVCB substance are expected to be unlikely to be subject to metabolism by intracellular enzymes because the ionized nature of the substance will limit entry to cells. AMES testing with and without S9 fractions gave similar negative results in terms of revertants and toxicity. These results suggest the substance is unlikely to be metabolically activated to toxic intermediates. Even if there is any metabolism, it is expected to be minimal and the absence of any increase in liver weight or change in serum enzyme levels suggests only a low level of metabolism.

Conclusions:

Absorption is inherently likely during dermal exposure to the registered substance but will be reduced by risk mitigation measures designed to protect humans from corrosive properties (workers) or reduced substance concentration (consumers). Distribution is expected to be via blood circulation to the liver and other tissues. The substance is unlikely to be metabolically activated to toxic intermediates and rapid exretion via the kidneys is expected. Elimination of non-absorbed material is predicted to be via the feces.

Description of key information

Absorption is inherently likely during dermal exposure to the registered substance but will be reduced by risk mitigation measures designed to protect humans from corrosive properties (workers) or reduced substance concentration (consumers). Distribution is expected to be via blood circulation to the liver and other tissues. The substance is unlikely to be metabolically activated to toxic intermediates and rapid exretion via the kidneys is expected. Elimination of non-absorbed material is predicted to be via the feces.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

The following assessment of the toxicokinetic profile of the registered substance is based on the physical chemical properties and toxicity data on the substance. No experimentally derived ADME data are available for this substance.

 

Substance Characterization

Analytical characterizations show that this substance meets the definition of a UVCB. This substance is a colorless liquid at ambient laboratory temperature (20°C). The generic structure is available and MW is 620 g/moL, but the oligomers exist with a range of diol units from 1 – 10, giving a wide range of possible molecular weights, as described in the purity summary.

 

Physical Chemical Properties

Molecular weight (MW), water solubility, log Kow, and vapor pressure are key physical chemical properties for assessing the toxicokinetics of a substance. This substance is a liquid, the MW is given as an average of 620, but with a range of 196.18 to 2015.14, where approximately 40.1% of the substance has a MW of 206.22. The substance has a wide range of solubilities in water with an average of 3.19 g/L equivalent test item concentration. The partition coefficient (log Pow) also has a range of values from -1.02 to 4.65; the LogPow of the component with the CAS#54439-60-0 (~40% of the substance) is reported to be 3.28. The substance has a low vapor pressure of 7.24 x 10-2Pa. The substance has also been shown to hydrolyze in water at pH4, 7 and 9, and at temperatures of 10, 20 and 30°C, but most significantly at pH7 and 30°C, consequently the toxicokinetic predictions based on the parent substance may not be relevant to that of the hydrolytic products produced in the intestine. The substance has a low pH of 2.62, which indicates a potential for ionization.

 

Exposure Routes

The potential for exposure to this substance is limited by its use and physical chemical properties. The dermal contact route is considered to be the primary route of occupational exposure. Inhalation exposure is expected to be limited because this substance has a low vapor pressure. Because of the use pattern oral exposure is not an anticipated route of exposure, either to workers or the general public.

Adsorption

Dermal route

The dermal absorption of the main components of this substance is expected to be limited because the MW of even the smallest component is >100. However, the solubility in water and the lipid solubility indicate that dermal absorption of the substance is favored and may be enhanced by iif the paste becomes liquid. ECHA endpoint specific guidance chapter R.7C indicates that for substances with a MW <100 are favored for absorption and if water solubility is >10g/L and a Log PoW <0, then the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. This substance has physicochemical properties that mostly favor dermal absorption. Consequently, absorption via the dermal route is expected to be moderate, which is supported by the toxicity data; the substance is corrosive to skin. Furthermore, damage to the skin caused by its corrosive nature may further enhance dermal absorption. However, the dermal acute toxicity of the substance shows that the LD50 is greater than 2000 mg/kg, which may indicate that dermal absorption is low, or that the substance has low intrinsic toxicity. Based on the toxicological evidence, the test substance is likely to be absorbed following dermal application, however, because of its corrosive properties, dermal exposure is expected to be limited or controlled under normal use conditions.

Oral route

Absorption in the gastrointestinal tract is predominantly influenced by the water solubility, ionization state, lipophilicity, and molecular weight of a chemical.  The substance is soluble in water and has a lipid solubility that is inside the Log Pow range of -1 to 4 that is considered favorable for absorption. The MW covers a wide range, but a significant proportion of the substance has a MW below 500, which may permit passive absorption. Furthermore, the substance is hydrolyzed at the temperature and pH conditions of the intestine, which may further promote absorption. However, the substance components are ionizable, which is generally considered to inhibit absorption, depending on the pKa. The results of an acute oral toxicity study indicate no evidence of systemic toxic effects at 2000 mg/kg/bw, which may be because the substance has low absorption or because of low intrinsic toxicity. The results of repeated dose toxicity, reproductive toxicity, and developmental toxicity studies all indicate that the substance, or some components of the substance, are absorbed. In the 28-day repeated dose study there was evidence of effects in the male kidney (hyaline droplets). Whilst these effects were not adverse and reversible, they do indicate that there was absorption, systemic exposure, and excretion via the kidney. Local toxicity was observed as hyperplasia and hyperkeratosis in the non-glandular stomach. In a reproductive screening toxicity study, there were effects at the high dose level on post-natal survival, pup bodyweights and bodyweight gains. These effects were mirrored in a developmental toxicity study where there were reductions in fetal bodyweight at the high dose level. There were no histopathological correlates for these observations and no obvious toxicological mode of action. Furthermore, there were no toxicological effects on the parental animals except for lower food consumption by the females in the reproductive toxicity study, and the probable local toxicity/irritation to the non-glandular stomach. At face value, the effects on the offspring can be taken as evidence of absorption and systemic exposure.

Inhalation route

The substance is a paste at ambient temperature and has low vapor pressure, therefore the potential for inhalation exposure via vapor is considered to be highly unlikely.

Distribution

Once this substance (or at least the absorbable components) is absorbed, it is expected to be circulated via the blood to the liver and other tissues. Due to its ionized nature it is predicted not to be significantly absorbed by the cells of the organs and tissues that it contacts except for the kidney. The substance is unlikely to bioaccumulate because of its generally low lipid solubility.

 

Metabolism

The absorbed components of this UVCB substance are expected to be unlikely to be subject to metabolism by intracellular enzymes because the ionized nature of the substance will limit entry to cells. AMES testing with and without S9 fractions gave similar negative results in terms of revertants and toxicity. These results suggest the substance is unlikely to be metabolically activated to toxic intermediates. Even if there is any metabolism, it is expected to be minimal and the absence of any increase in liver weight or change in serum enzyme levels suggests only a low level of metabolism.

 

Elimination

Because of the physicochemical characteristics of this substance any absorbed material is expected to be excreted rapidly via the kidneys and non-absorbed material will be excreted via the feces.