Reaction mass of N-(2-hydroxyethyl)alkyl] alkylamide and glycerol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Objective of study:

other: QSAR medelling of metabolism etc.

GLP compliance:

no

Remarks:

The study was carried out in compliance with the OECD Guideline 428 in a GLP facility but was not subjected to full GLP auditing.

Test material

Test material information

Constituent 1

Test material form:

liquid

Details on test material:

Chemical Name: N-[2-(2-Hydroxyethoxy)ethyl]acetamide
CAS No.: 118974-46-2
Batch: 27191705
Purity: 82% (dose calculation was adjusted to puriy)
Appearance: Pale to yellow liquid
Expiry Date: 16 June 2017
Storage Conditions: At room temperature
Stability in Solvent: Stable in water (not quantified)
Purpose of Use: Industrial chemical

Results and discussion

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Profiling:

Substance	DGA (Diglycolamine acetamide)
CAS	118974-46-2
IUPAC	N-[2-(2-hydroxyethoxy)ethyl]acetamide
SMILES	CC(NCCOCCO)=O
Molecular formula	C6H13NO3
Molecular weight	147.17
Physical state
Density  (ACD/Labs)	1.071±0.06 g/cm^3; Condition: Temp: 20 °C Press: 760 Torr
Solubility: Avg Sol	146 g/L (SwissADME)
EpiSuite(WSKOW v1.42)	1e+006 mg/L
(WATERNT v1.01)	1e+006 mg/L
Solubility: (Chemaxon)	Intrinsic solubility:0.42mg/ml (for all pH between 1.7 – 12)
Solubility: (ACD/Labs)	Very Soluble, 999 g/L (6.79 mol/L) in unbuffered Water pH 6.90
pKa:  (ACD/Labs)	14.38±0.10: Most Acidic
	-0.61±0.70: Most Basic
pKa:  (Chemaxon)	Strongest acidic pKa 15.03 (-OH)
	Strongest basic pKa -1.63 (=O)
logPow (Avg LogPow)	-0.33
EpiSuite(KOWWIN v1.68)	-1.9443
(ACD/Labs)	-1.341±0.392
logD  (Chemaxon)	-1.54 for all pH between 1,7 – 12
(ACD/Labs)	-1.34 for all pH between 1 - 10
Mp  (EPIWIN)	101.08°C
bp  (EPIWIN)	322.14 °C
Vp (25°C) (EPIWIN)	0.000782 Pa
Henry 25°C  (EPIWIN)	1.88E-009 (bond estimate)
Pa.m3/mole	Incomplete (group estimate)
Reactivity profile
Reactivity profile – General mechanistic	-    Cramer: High (Class III)
Reactivity profile – Endpoint specific	-    Aquatic tox MOA by OASIS: Basesurface narcotics
	-    Aquatic tox class ECOSAR: Amides
	-    in vivo mutagenicity (Micronucleus) alerts by ISS: H-acceptor-path3-H-acceptor
Reactivity profile – Toxicological	-     Repeated dose (HESS): Diethylene glycol (Renal toxicity) Alert (based on the similarity to the target compound)
Dermal penetration coefficient Kp (est)	2.79E-05 cm/h (SwissADME)
	1.19E-05 cm/h (Dermwin v2.02)
(SwissADME):	High GI-absorption / fulfills Lipinski’s rule of five
Bioavailability score	Prob. F>10% = 0.55
log Pow (≤ 5)	-0.33
H-acceptors (≤10)	3
H-donors (≤5)	2
mw≤ 500 D)	147.17 g/mol
Rotatable bonds (≤10)	6
Atom count (20-70)	23 (10 heavy)
PSA (≤140Å^2)	58.56 Ų

Name, Structure, Molecular formula, molecular weight: From CAS registry

ACD/Labs: all atTemp: 25 °C- Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2019 ACD/Labs)

Alternative source: ChemAxon viahttps://chemicalize.com/

EPIWIN, KOWWIN v1.68; WSKOW v1.42, WATERNT v1.01 and Dermwinv2.02 from EPI Suite v.4.1

Avg LogPow (Consensus logPow); Avg. solubility (based on Avg LogS from ESOL, Ali, and SILICAS-IT) dermal Kp:http://www.swissadme.ch/index.php
Reactivity profile: QSAR Toolbox v.4.3

Dermal penetration coefficient:

- DermWin: log Kp = -2.80 + 0.66 log Kow - 0.0056 MW (water Kp (predicted): 0.00015 cm/hr)

- SwissADME: model by model by Potts and Guy, 1992, applying XLOGP3 as lipophilicity descriptor

 

Applicant's summary and conclusion

Conclusions:

Results from molecular profiling and QSAR evaluations indicate a general lack of mechanistic and endpoint specific alerts and an overall low toxicity.
Profiling indicates high gastro-intestinal absorption, whereas dermal absorption for this small hydrophilic substance is expected to be low.

Executive summary:

Results from molecular profiling indicate high water solubility, low logPow and reasonable uptake by oral route and probably very limited uptake via dermal route (dermal penetration coefficient is lower than that of water).

The predicted transformation/metabolism possibilities by QSAR Toolbox (v 4.3) do not list substances of specific concern (specifically not acetamide) among the likely metabolites: Hydrolysis simulation indicate possible split into acetic acid and diglycolamine, or even ethanediol and n-2-hydroxyethylacetamide, but not Acetamide. Acetamide is a non-genotoxic carcinogen in rodents, leading to hepatocellular carcinomas in rats, and malignant lymphomas in mice.

 

On overall, the profiling and QSAR results indicate no interaction to DNA, no mutagenicity, no carcinogenicity and an overall low toxicity.Only (moderate) ocular irritation has been predicted (TOPKAT and ACD/ToxSuite), and possibly skin irritation (CAD/ToxSuite).

A few models (HESS and a prototype warning in DEREK) point at the presence of Diethylene glycol in the DGA structure, a substance that is known to cause Nephrotoxicity, but no firm statements are done in that respect.

There is one VEGA model that predicts possible developmental toxicity. Although high reliability is indicated, this VEGA model reports also a lack of comparable structures with experimental data in the data base. Additionally, the data from the presented most comparable structures are not convincing and show disconcordant results. No other models for developmental toxicity (another in VEGA, TOPKAT and DEREK) indicate a concern for developmental toxicity.

 

None of the general mechanistic and endpoint specific profilers that are relevant for skin sensitization triggered a concern to the DGA structure. Of the relevant QSARs, TOPKAT and DEREK do not predict a concern for sensitization. Only one of the two VEGA models predict possible skin sensitization, but this prediction is not reliable as the DGA structure is outside the applicability domain of the model.

All in all, there are no concerns for skin sensitization. The Read-across analysis executed via the automated work process for "Skin sensitization" in QSAR Toolbox results to a negative prediction. (The prediction is based on 4 values, all negative)

 

The available data on the reaction mass of N-[2-(2-hydroxyethoxy)ethyl]acetamide [DGA] and glycerol, are in general agreement to the predicted properties.

The various performed in vitro studies all show no cytotoxicity up to the maximum tested concentrations. Even the alerts for skin and eye irritation by some QSARs are not supported. Data from in vitro testing for skin and eye irritation clearly showed that the product does not possess an irritating potential. Additionally, in vitro testing further confirmed that the product is not a sensitizing to skin and is not mutagenic or cytogenic.

Finally, a later performed repeated dose study with reproduction screening (OECD 422) that was required under European chemical legislation REACH, confirmed low toxicity as no adverse effects were observed in testing in rats up the limit dose of 1000 mg/kg bw/day.