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

Acute Toxicity: oral

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Administrative data

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

9th November 2015

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

Principles of method if other than guideline:

Background
Methods
i. Profiling - OECD QSAR Toolbox (v3.3)
ii. DEREK NEXUS (v.4.1.0)
iii. VegaNIC (v.1.1.1)
iv. TOPKAT (Discovery Studio client 3.1)
v. ACD/ToxSuite 2.95
vi. ECOSAR (v.1.11)

GLP compliance:

no

Test type:

other: QSAR

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

Specific details on test material used for the study:

DGA-Acetamide; CAS: 118974-46-2
N-[2-(2-hydroxyethyl)ethyl]acteamide [IUPAC]
Structure: CC(=O)NCCOCCO

Test animals

Species:

rat

Details on test animals or test system and environmental conditions:

As data is based on QSAR analysis, strain and sex, as well as environmental conditions are are not specified.

Administration / exposure

Route of administration:

oral: gavage

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 5 000 mg/kg bw

Based on:

other: This is based on consistent results of QSAR models,

Remarks on result:

other: based on QSAR model predictions

Any other information on results incl. tables

Profiling

The various Reactivity profiles in QSAR Toolbox basically show little or no concerns. The only concerns reported are “in vivo mutagenicity (Micronucleus) alerts by ISS” based on “H-acceptor-path3-H-acceptor”. This involves the presence oftwo bonded atoms connecting two H-bond acceptors in the structure, which is rather unspecific. (Most of the l substances showing this alert have negative in vitro mammalian cell micronucleus test results).

There is one additional repeated dose toxicity alert from HESS for renal toxicity. This is based on the structural similarity to Diethylene glycol, which has is known to cause nephrotoxicity. (Dice, atom centered fragment indicate a 58.85% similarity between DGA and Diethylene glycol).

Metabolism of DGA is not expected to occur in large extend. The substance is expected to be poorly absorbed from skin, and relatively rapidly excreted via urine.

On overall, the available information does not support a concern for the formation of Acetamide from DGA-Acetamide. All available reported examples of N-Dealkylation from the aldehyde involve tertiary amine structures, and de-alkylation of (very) short alkyl groups from the amine, and involve structures that involve lipophilic parts, generally aromatic rings. The DGA-Acetamide structure however involves a secondary amine that is negatively linked to this metabolic reaction, a diethylene glycol part rather than a short alkyl chain, and no aromatic or cyclic part.

Hydrolysis by hydrolase activity on the other hand is a commonly observed reaction for amide structures as found in DGA-Acetamide. Actual rate is uncertain, but for metabolic route it is considered more likely.

DEREK:

According to DEREK the structure does not contain specific hazardous elements. More specifically, both genotoxicity and sensitization are predicted to be negative. Based on the di-ethylene glycol moiety in the structures, an alert is fired for possible bone marrow toxicity and nephrotoxicity. Further, ‘Nothing else to report’.

VEGA

VEGA models in general predict low concerns for hazards.

TOPKAT

On overall the TOPKAT models predict DGA to be of low toxicity. Of the many models on carcinogenicity, there is only one resulting to a positive outcome (FDA mouse male), whereas all others are negative. The overall WoE rodent carcinogenetic model predicts ‘Non-Carcinogen’. Other toxicity models show a low toxicity potential. The only hazard predicted is a moderate eye irritation.

ACD/ToxSuite

ACD/ToxSuite also predicts low toxicity. The only potential hazard indicated are possible skin and eye irritation. This is on the basis of comparison to Aliphatic monohydroxy alcohols, that in majority are irritant to skin and eye

ECOSAR

ECOSAR predicts low aquatic toxicity for DGA, based on evaluations both for the QSAR substance categories ‘Amides’ and ‘Neutral organics’.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

QSARs predict an acute LD50 > 5000 mg/kg bw

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 (dermalpenetration coefficientis 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.

On overall, the profiling and QSAR results indicate no interaction to DNA or protein binding, no mutagenicity, no carcinogenicity and a general low toxicity. Only (moderate) ocular irritation has been predicted, although results from available BCOP study indicates a lack of irritating potential.

All in all, a low toxicity profile is indicated for the structure.

The QSAR data for acute (oral) toxicity was assessed in TOPKAT (DiscoveryStudio 2019, Toxicity Prediction) and ACD/ToxSuite (Tox Boxes v 2.9).

TOPKAT models indicate low acute toxicity by both oral and inhalation route in the rat: Oral LD50 rat 5399 mg/kg bw, and Inhalational LC50 in rat is predicted at 5270 mg/m3/h.

ACD/ToxSuite model predicted comparable low toxicity, with a rat oral LD50 value most likely to exceed 5000 mg/kg, and predicts an acute toxicology classification Cat 5 or non-toxic LD50 >2000mg/kg with a high probability score of 0.908.

Based on this information acute oral toxicity testing has not been done.  This has also taken into consideration that this substance is sold as a cosmetic ingredient.