Phosphonic acid, mixed C12-20-alkyl and C14-18-unsatd. alkyl derivs.

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

January 2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: On the basis of experimental data and considering general principles and knowledge the basic toxicokinetic properties were concluded with sufficient certainty.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: Expert Statement in IUCLID 5 (RSS)

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The basic toxicokinetic behaviour was assessed based on the known properties of the submission item by applying generally known and accepted principles.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phosphonic acid, mixed C12-20-alkyl and C14-18-unsatd. alkyl derivs.

EC Number:

300-326-6

EC Name:

Phosphonic acid, mixed C12-20-alkyl and C14-18-unsatd. alkyl derivs.

Cas Number:

93925-25-8

Molecular formula:

Complex

IUPAC Name:

Phosphonic acid, mixed C12-20-alkyl and C14-18-unsatd. alkyl derivs.

Test material form:

liquid: viscous

Results and discussion

Preliminary studies:

Physicochemical properties influencing the toxicokinetics are the water insolubility (< 0.1 mg/L), the irrelevantly low vapour pressure (0.00043 Pa at 25 °C), the very high lipophilicity (Log Kow > 9.4), the molecular weight range between 369.25 and 605.5 g/mol and the absence of any dissociation, pH-effects, corrosive or irritant properties.
No treatment related changes were observed in the 28 d repeated dose subacute toxicity or in the subacute oral reproduction/developmental toxicity study in rats (NOAEL ≥ 1000 mg/kg bw per d) and an acute dermal toxicity test (up to 2000 mg/kg bw).
The submission item is deemed to show low bioaccumulation and was found readily biodegradable.

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Orally and dermally low; inhalation negligible

Main ADME results 2

Type:

distribution

Results:

Widely with tendency to shift into fatty tissues

Main ADME results 3

Type:

metabolism

Results:

Intense, therefore any accumulation unlikely

Main ADME results 4

Type:

excretion

Results:

Predominantly unchanged via faeces

Toxicokinetic / pharmacokinetic studies

Details on absorption:

It is generally accepted that the optimal level of lipophilicity for the transepithelial passage is about Log Kow 3.5 while excessive hydrophoby is expected to result in low intestinal epithelial permeability and in low oral absorption. The lack of dissociation in the range of 0-14 pH supports the assumption that no speciation will influence the fugacity of the submission item. Due to the absence of irritating properties it can be expected that the submission item will not produce any local effects, which could increase the permeability. The assumption of low oral absorption is supported by the absence of subacute rodent toxicity as no difference to the control was observed in two independent studies. Accordingly low dermal absorption is supported by the absence of effects in the acute dermal toxicity study up to 5000 mg/kg bw. Inhalation seems an irrelevant route of exposure due to the negligible vaporization. The formation of any airborne particles is unlikely in the supported uses. In summary orally and dermally low absorption can be expected, while inhalation is considered an irrelevant exposure route.

Details on distribution in tissues:

The molecular weight range of the submission is in a comparatively low range, which is associated with generally wide distribution. The water insolubility in combination with the lack of dissociability will lead to a tendency of partitioning into fatty tissues and organs. Thus wide tissue distribution with tendency to shift into fatty tissues can be assumed.

Details on excretion:

Due to the water insolubility, kidney elimination will play an insignificant role, while unchanged excretion in the faeces seems likely. Only an insignificant fraction is expected to be exhaled due to the low vapour pressure.

Metabolite characterisation studies

Details on metabolites:

Read-across to comparable compounds suggests important metabolization, which is supported by the finding of microbial transformation leading to ready biodegradation. Similar chemicals show low BCF however having high Kow values (see waiving justification for aquatic bioaccumulation). Therefore a high metabolic rate can be expected. The UVCB may undergo a cleavage from activated phospholipases in long-chain alcohols. Alcohols could thereafter be oxidized by the alcohol dehydrogenase to aldehyde and by aldehyde dehydrogenase enzymes to fatty acids. In the liver the fatty acids are expected to be broken down by β-oxidation. This assumption is supported by the OECD QSAR Toolbox version 3.0 results (CATABOL algorithm) for low and high molecular weight representatives of the UVCB, where hydrogenphosphonates and the respective alcohols, aldehydes and carbonic acids were predicted. Therefore intense metabolism seems likely and low half-lives in biota can be expected.

Applicant's summary and conclusion

Executive summary:

The basic toxicokinetic behaviour of the test item can be assessed based on the known properties and available toxicity studies of the submission item by applying generally known and accepted principles including QSPR calculation. Physicochemical properties influencing the toxicokinetics are the water insolubility (< 0.1 mg/L), the irrelevantly low vapour pressure (0.00043 Pa at 25 °C), the very high lipophilicity (Log Kow > 9.4), the molecular weight range between 369.25 and 605.5 g/mol and the absence of any dissociation, pH-effects and corrosive or irritant properties. No treatment related changes in the test animals were observed during the 28 d repeated dose subacute toxicity or in the oral reproduction/developmental toxicity study in rats (NOAEL > 1000 mg/kg bw /d) and an acute dermal toxicity test indicating no effects up to 2000 mg/kg bw. The submission item is deemed to show low bioaccumulation in aquatic food chains and was found readily biodegradable.

Absorption: It is generally accepted that the optimal level of lipophilicity for the transepithelial passage is about Log Kow 3.5 while excessive hydrophoby is expected to result in low intestinal epithelial permeability and in low oral absorption. The lack of dissociation in the range of 0-14 pH supports the assumption that no speciation will influence the fugacity of the submission item. Due to the absence of irritating properties it can be expected that the submission item will not produce any local effects, which could increase the permeability. The assumption of low oral absorption is supported by the absence of subacute rodent toxicity as no difference to the control was observed in two independent studies. Accordingly low dermal absorption is supported by the absence of effects in the acute dermal toxicity study up to 2000 mg/kg bw. Inhalation seems an irrelevant route of exposure due to the negligible vaporization. The formation of any airborne particles is unlikely in the supported uses. In summary orally and dermally low absorption can be expected, while inhalation is considered an irrelevant exposure route.

Distribution: The molecular weight range of the submission is in a comparatively low range, which is associated with generally wide distribution. The water insolubility in combination with the lack of dissociability will lead to a tendency of partitioning into fatty tissues and organs. Thus wide tissue distribution with tendency to shift into fatty tissues can be assumed.

Metabolism: Read-across to comparable compounds suggests important metabolization, which is supported by the finding of microbial transformation leading to ready biodegradation. Similar chemicals show low BCF however having high Kow values (see waiving justification for aquatic bioaccumulation). Therefore a high metabolic rate can be expected. The UVCB may undergo a cleavage from activated phospholipases in long-chain alcohols. Alcohols could thereafter be oxidized by the alcohol dehydrogenase to aldehyde and by aldehyde dehydrogenase enzymes to fatty acids. In the liver the fatty acids are expected to be broken down by β-oxidation. This assumption is supported by the OECD QSAR Toolbox version 3.0 results (CATABOL algorithm) for low and high molecular weight representatives of the UVCB, where hydrogenphosphonates and the respective alcohols, aldehydes and carbonic acids were predicted. Therefore intense metabolism seems likely and low half-lives in biota can be expected.

Excretion: Due to the water insolubility, kidney elimination will play an insignificant role, while unchanged excretion in the faeces seems likely.