2-dimethylaminoethyl methacrylate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2020

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

Three male rats were intravenously administered MADAME at a targeted dose level of 5.66 mg/kg (36 µmol/kg) using sterile saline as the dose vehicle. After dose administration, blood samples (~200 μL) were collected at 5, 10, 30, 60, and 180 minutes into individual pre-weighed glass vials containing ethyl acetate (600 μL) acidified with 10% trifluoroacetic acid (TFA). After vortexing and subsequent centrifugation, the blood extracts underwent quantitative analysis for MADAME by gas chromatography with tandem mass spectrometry (GC/MS-MS).

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (Kingston, New York)
- Age at study initiation: 9-12 weeks
- Weight at study initiation: 194-197 g
- Housing: singly in glass Roth-type metabolism cages
- Diet (e.g. ad libitum): LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in pelleted form, ad libitum
- Water (e.g. ad libitum): Municipal water, ad libitum
- Acclimation period: 7d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C with a range of 20°C-26°C
- Humidity (%): 50% with a range of 30-70%
- Photoperiod (hrs dark / hrs light): 12-hour light/dark (on at 6:00 a.m. and off at 6:00 p.m.)

Route of administration:

intravenous

Vehicle:

other: Intralipid 20%

Details on exposure:

An appropriate amount of MADAME was added to sterile physiological saline to obtain the appropriate dose concentration using aseptic technique. The amount of dose solution administered was targeted at ~2.5 mL/kg bw and injected over ~1 minute for a corresponding injection rate of ~0.5 mL/minute. The dose solution was administered at room temperature (19-25 °C) and used within 24 hours of preparation.

Duration and frequency of treatment / exposure:

single iv treatment

Dose / conc.:

5.66 mg/kg bw/day (nominal)

Remarks:

corresponds to 36 µmol/kg

No. of animals per sex per dose / concentration:

3 males

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

no

Details on study design:

- Dose selection rationale: previous studies of this type have used similar equimolar ratios

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: 5, 10, 15, 30, 60 and 180 minutes post-dosing

Statistics:

Descriptive statistics were used, i.e., mean ± standard deviation, where applicable. All descriptive statistic calculations were conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington) spreadsheets in full precision mode (15 digits of accuracy). Pharmacokinetic parameters that were calculated for blood used the pharmacokinetic computer modeling program PK Plus (v. 9.6, Simulation Plus, Inc., Lancaster, California, United States of America).

Preliminary studies:

The solubility of MADAME was tested at up to 10 mg/mL in Intralipid 20% and sterile saline. The test material was soluble in both vehicles at this concentration and saline was chosen as the vehicle.

Key result

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: < 2 min-1

Test no.:

#1

Toxicokinetic parameters:

AUC: 208 µg-min/g

Test no.:

#1

Toxicokinetic parameters:

other: <1% of the dose remaining in the blood 5 minutes post-intravenous administration

Metabolites identified:

not measured

The resulting blood time course showed that MADAME was quickly hydrolyzed with  < 1% of the dose remaining in the blood 5 minutes post-intravenous administration. Further pharmacokinetic analysis of the blood concentrations of MADAME showed that the compound exhibited single-phase elimination (i.e. half-life; t_½). The average calculated t_½value was < 2 min^-1and the average area under the curve (AUC_0-t) value was approx. 208 µg-min/g. 

Conclusions:

Overall, the analysis of the blood pharmacokinetics indicated that the parent test material is rapidly removed from blood circulation (i.e. blood compartment)in vivo. This finding is in line with the observations for similar and well-analysed methacrylates. Hence, these data support a pharmacokinetics-based Read-Across for MADAME to the metabolites methacylic acid (CAS No. 79 -41 -4) and 2- dimethyl aminoethanol (CAS No. 108 -01 -0) respectively. For more details please refer to the "Read-across justification based on RAAF 2019" as attached to this IUCLID Chapter 7.8.1 and 7.8.2.

Executive summary:

This study was performed to determine the applicability of a pharmacokinetics-based Read-Across approach for 2-(dimethylamino)ethyl methacrylate (MADAME) to other well-studied methacrylates by evaluating the hydrolysis and pharmacokinetic characteristics of the test materialin vivo. Under thesein vivoconditions less than 1% of the administered dose (on average) remained in the blood 5 minutes post-dosing which indicates that MADAME was rapidly removed from circulating blood. Pharmacokinetic analysis of the blood concentrations of MADAME showed that the compound exhibited a single-phase elimination in which the average t_½value was below 2 min. The average AUC_0-tvalue for MADAME was approx. 208 µg-min/g. Based on the properties of the quick hydrolysis and pharmacokinetics of MADAME in vivo, these data support a pharmacokinetics-based Read-Across for MADAME with other similar and well-studied methacrylates.

Description of key information

MADAME is likely to be readily absorbed by all routes. Due to the low vapour pressure, the dermal route is the primary route of exposure, since inhalation is unlikely. The ester is rapidly hydrolysed by carboxylesterases to methacrylic acid (MAA) and 2 -dimethylamino ethanol (DMEA/DMAE). The primary metabolite, MAA, is subsequently cleared rapidly from blood by standard physiological pathways, with the majority of the administered dose being exhaled as CO2. Based on physicochemical properties, no potential for bioaccumulation is to be expected.

Absorption

Oral absorption

The physicochemical properties of MADAME i.e. the octanol/water partition coefficient (log P value of 1.13), the high water-solubility and the molecular weight of 157.21 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion.

For chemical safety assessment an oral absorption rate of 100% is assumed as a worst-case default value in the absence of other data.

Dermal absorption

For chemical safety assessment, a dermal absorption rate of 100% was assumed as worst case default value.

Inhalation absorption

Due to the low vapourpressure of MADAME (0.58hPa at 20°C), exposure via inhalation is unlikely. For chemical safety assessment aninhalativeabsorption rate of 100% is assumed as a worst case default value in the absence of other data.

Distribution

As a small molecule a wide distribution can be expected. No information on potential target organs is available.

Metabolism and excretion

Ester hydrolysis induced by carboxylesterases has been established as the primary step in the metabolism of methacrylate esters. Carboxylesterases are a group of non-specific enzymes that are widely distributed throughout the body and are known to show high activity within many tissues and organs.

The rapid hydrolysis of MADAME could be proofed by an experimentally in vivo study in rats which reveals a half-life of less than 2 minutes for MADAME (DOW 2020). Ester hydrolysis of MADAME results in MAA and the respective alcohol DMEA/DMAE.

 

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Supporting information:

Furthermore, two in vitro studies investigating the metabolism of the substance were reviewed and are described below.

The test substance was rapidly hydrolysed to methacrylic acid (MAA, CAS No. 79-41-4) and N,N-dimethylaminoethanol (DMAE, CAS No. 108-01-0) when incubated with simulated saliva or simulated intestinal fluid in vitro. 90% degradation was observed in simulated saliva after 4 hours at 37 °C, 86% degradation after incubation with simulated intestinal fluid for 4 hours at 37°C. Degradation was below 8% after incubation with simulated gastric fluid for 4 hours at 37°C (Atochem, 1994; cited in: OECD SIDS, 07/2003).

Small quantities of methacrylates may readily be metabolised by saponification into the alcohol and methacrylic acid. The latter may form an acetyl-CoA derivative, which then enters the normal lipid metabolism (Clayton/Patty, 1993-1994).

Based on the available physical and chemical information on the test substance and the results from available toxicity studies the following additional assumptions about the toxicokinetic behaviour of the test substance can be made:

There are no substance-specific data available considering dermal absorption. However, the established dermal LD50 value of > 2000 mg/kg in rabbits (Atochem, 1992) is suggestive of a limited dermal absorption of the test substance.

Basically, it is assumed that a certain absorbability of the test substance in the gastro-intestinal tract is given. This assumption is based on systemic effects detected at 1000 mg/kg in an oral repeated dose toxicity study in rats (MHW Japan, 1998).

The test substance is considered to have a low bioaccumulative potential based on its log Pow of 1.13 at 25°C (CERI Japan, 1997).

Discussion on bioaccumulation potential result:

The available data are limited. Two available studies were reviewed and are described below. The study by Atochem (1994) was assessed based on its citation in the OECD SIDS 2005 only. No in vivo study was available for assessment.

The substance was rapidly hydrolysed to methacrylic acid (MAA, CAS No. 79-41-4) and N,N-dimethylaminoethanol (DMAE, CAS No. 108-01-0) when incubated with simulated saliva or simulated intestinal fluid in vitro. 90% degradation was observed in simulated saliva after 4 hours at 37°C, 86 % degradation after incubation with simulated intestinal fluid for 4 hours at 37°C. Degradation was below 8% after incubation with simulated gastric fluid for 4 hours at 37°C (Atochem, 1994; cited in: OECD SIDS, 07/2003).

Small quantities of methacrylates may readily be metabolized by saponification into the alcohol and methacrylic acid. The latter may form an acetyl-CoA derivative, which then enters the normal lipid metabolism (Clayton/Patty, 1993 -1994).