Reaction mass of Dimethyl [3-[(hydroxymethyl) amino]-3-oxopropyl] phosphonate and Dimethyl (3-amino-3-oxopropyl)phosphonate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

weight of evidence

Study period:

11.04.2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert statement

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

other: according to the requirements of Annex VIII of the EC Regulation 1907/2006

GLP compliance:

no

Details on absorption:

TOXICOKINETIC BEHAVIOUR
No studies are available regarding the absorption, distribution, metabolism or excretion properties of DMPPA_701-402-5 in animals or humans following dermal, oral or inhalation exposure. Thus, the toxicokinetic behaviour of DMPPA_701-402-5 was assessed using the OECD QSAR Application Toolbox v2.21 to make a qualitative prediction of metabolites formed in liver and skin as well as applying knowledge from actual toxicological studies on the substance.

Absorption
Oral route
In a 5-day subacute range-finding oral gavage study in the rat, doses of up to 1000 mg/kg bw/day did not result in clinical signs of toxicity or mortality. Further, in the 28-day study the NOAEL was >1000 mg/kg bw/day. At dose levels of up to 1000 mg/kg bw/day, there were no signs of toxicity or treatment-related changes in the haematological, clinical biochemical, urinalysis, macroscopic and microscopic parameters. No conclusion can be derived, if completely low oral uptake and bioavailability and/or very low toxicity of the substance are the reasons for the findings.Thus, in addition, the OECD QSAR Application Toolbox v2.2 was used to apply Lipinski's Rule of Five. DMPPA was predicted to be orally bioavailable based on these rules.

Inhalation route
The 4-hour acute inhalation LC50 of DMPPA was determined to be > 2.71 mg/L air (nominal 4.83 mg/L air), the highest achievable concentration in the study. There were no deaths, no effects on body weight gain and no clinical signs of toxicity in the study. Gross findings at necropsy consisted of isolated dark foci on the left or right caudal lung lobe of 2 males and 2 females. The findings do not suggest any concerns over inhalation route toxicity. The only effects observed in the study were local in nature in the lungs. Based on this information, no conclusion regarding the inhalation absorption and bioavailability is possible. However, an estimation of the absorption after inhalation can be based on the substance-specific physical-chemical properties. As soon as aerosol particles of aerodynamic diameters of 3 μm are generated (as done in the acute inhalation study) the substance can reach the alveolar region of the respiratory tract. As a hydrophilic liquid with high water-solubility, DMPPA_701-402-5 is regarded to readily diffuse/dissolve into the mucus lining the respiratory tract. Alike, the substance would be readily soluble in blood. Crossing of the respiratory tract epithelium membranes can be limited due to the relatively low
lipophilicity of DMPPA_701-402-5 (logP < -1). However, showing a MW of around 200, the substance might be available for absorption through aqueous pores. As the prediction for the oral route indicates the potential for absorption following ingestion,
absorption of the substance following inhalation is likely.

Dermal route
The acute dermal LD50 of DMPPA_701-402-5 in the rat was > 2000 mg/kg bw. The findings indicate limited toxicity hazard from dermal exposure, which is further confirmed by the absence of irritation in an in vivo skin irritation study and the absence of sensitization in a skin sensitization study (GPMT). The high water solubility and the low partition coefficient (logP < -1) indicates low dermal permeability. Alike, according to the Danish (Q)SAR database2, dermal absorption is predicted to be low (0.001 mg/cm²/event).

Details on distribution in tissues:

Distribution of DMPPA_701-402-5 is estimated based on the substance-specific physico-chemical properties.As the substance has a moderate molecular weight, distribution in the body is expected to be relatively wide. Due to the high water solubility of the substance, the molecules might diffuse through aqueous channels and pores. Thus, DMPPA_701-402-5 is expected to be rapidly distributed into organs and tissues However, as DMPPA_701-402-5 is of low lipophilicity, its diffusion rate across membranes and into cells is regarded to be limited and the intracellular concentration is expected to be lower than in extracellular compartments. It is not expected to bioaccumulate.

Details on excretion:

Short-term toxicity studies with relatively large doses of DMPPA_701-402-5 suggest that absorbed DMPPA_701-402-5 and metabolites are rapidly eliminated without impact to the test animals. The physico-chemical properties of the metabolites as predicted by the OECD toolbox suggest that they are all water soluble and likely to be eliminated rapidly in urine.

Details on metabolites:

Metabolism
Potential metabolites of DMPPA_701-402-5 in the liver and skin were determined by the OECD toolbox v2.2 (Table 1). Six metabolites were predicted for the liver metabolism, nine metabolites for skin metabolism. Four metabolites were common in both, liver and skin metabolism (M1, M2, M3 and M4). M5 and M6 are predicted to be found only after metabolism in the liver whilst M7, M8, M9, M10 and M11 are predicted by skin metabolism only. The main predicted reactions in liver and skin involve cleavage and hydroxylation of one (M3) or both (M5) of the methyl ester bonds leading to the formation of methanol. Formation of aminomethanol and a propanoic acid compound is predicted to result from cleavage of the (hydroxymethyl) amino moiety with subsequent hydroxylation for M4 and M6. Formation of the 3-amino-oxopropyl group is only envisaged in the skin resulting in M7 and M9. Further investigation of the dimethyl phosphonate moiety identified one study which illustrates the potential metabolic pathway at the dimethyl phosphonate domain (Nomeir and Matthews, 1997). Fischer 344 rats and B6C3F1 mice were administered once orally 10 or 200 mg/kg bw 14C-labelled dimethyl phosphonate by gavage. Repeated dosing effects were investigated in rats administered a dose of 200 mg/kg bw 14C-labelled dimethyl phosphonate for 5 days. Dimethyl phosphonate was rapidly absorbed and there was limited evidence of bioaccumulation or saturation of absorption or elimination. The main metabolic pathway in rodents was determined to be demethylation of dimethyl phosphonate to monomethyl hydrogen phosphite (MMP) and further oxidation via formaldehyde to CO2 (Nomeir and Matthews, 1997). As an intermediate metabolite, formaldehyde is further oxidised to methanol or to CO2 (Figure 1). In addition, the release of formaldehyde via hydrolysis of N-methylol moiety has been documented (Ashby et al. 1985; Coley et al. 1995).

Conclusions:

No bioaccumulaton expected because of log KOW

Description of key information

The toxicokinetic behavior of DMPPA_701-402-5 was assessed. DMPPA_701-402-5 was predicted to be bioavailable by the oral and inhalation route, whereas bioavailability via the dermal route is predicted to be low. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

100

Additional information

The OECD toolbox v2.2 has been used to predict the metabolism of DMPPA_701-402-5, its metabolites and their expected physico-chemical properties and toxicokinetic behaviour. DMPPA_701-402-5 is regarded to be good bioavailable after uptake via the oral and inhalation route. Dermal absorption is expected to be low. DMPPA_701-402-5 as well as the predicted metabolites are expected to be widely distributed in the organism without potential of bioaccumulation. Excretion via urine is regarded to be the preferred way of elimination. There are clear indications from available toxicity studies that DMPPA_701-402-5 and its metabolites predicted with the OECD toolbox do not present a genotoxic hazard and significant toxicity in animals.