Butyl carbamate

Hydrolysis

Link to relevant study record(s)

Reference

Endpoint:

hydrolysis

Type of information:

(Q)SAR

Remarks:

Data estimated by Hydrowin v2.00 (EPISuite v 4.1); test substance was found to fall in the applicability domain of this method and results are adequate for the purpose of classification and labeling and/or risk assessment.

Adequacy of study:

key study

Study period:

2016

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 limited documentation / justification

Justification for type of information:

See below under 'Overall remarks, attachments' for applicability domain.

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs: Chapter R.6. QSARs and grouping of chemicals

Principles of method if other than guideline:

Base-catalyzed rate constant for carbamate is estimated using the below carbamate equation of HYDROWIN v.2.00 program of EPISuite v4.1:

log Kb = 2.3 Sum[sigma*{ R1+R2} ] + 0.96 Sum[sigmaX{ R1+R2} ] + 7.97 sigma*{ R3} + 2.81 sigmaX{ R3} - 0.275

Specific details on test material used for the study:

Input data for the model:
CAS: 592-35-8; or
SMILES: O=C(OCCCC)N

Estimation method (if used):

Carbamates are designated by the formula:   R1-N(-R2)-C(=O)-O-R3
HYDROWIN calculates a base-catalyzed rate constant for carbamates.  
Generally, two different equations are used. One equation applies to di-N-substituted carbamates and the other equation applies to all other carbamates.

The di-N-substituted equation is the following:

log Kb = 7.99 sigma*{R3} + 0.316 Sum[sigmaX{R1+R2}] + 3.14 Sum[Es{R1+R2}] + 0.442

The general carbamate equation is the following:

log Kb = 2.3 Sum[sigma*{R1+R2}] + 0.96 Sum[sigmaX{R1+R2}] + 7.97 sigma*{R3} + 2.81 sigmaX{R3} - 0.275

Therefore, considering the structure of butyl carbamate, which is not a di-N-disubstituted carbamate, the general equation equation is used by the program for the estimation.

Transformation products:

no

Key result

pH:

7

Temp.:

25 °C

DT50:

ca. 3 327 yr

Type:

other: base catalysed rate constant (Kb)

Remarks on result:

other: estimated data

Key result

pH:

8

Temp.:

25 °C

DT50:

ca. 333 yr

Type:

other: base catalysed rate constant (Kb)

Remarks on result:

other: estimated data

Key result

pH:

8

Temp.:

25 °C

Type:

other: base catalysed rate constant (Kb)

Remarks on result:

other: estimated data; Total Kb for pH > 8: 6.602E-5 L/mol-sec

Remarks:

for atom 2 (see details on results)

Details on results:

SMILES : O=C(OCCCC)N
CHEM : Carbamic acid, butyl ester
MOL FOR: C5 H11 N1 O2
MOL WT : 117.15
--------------------------- HYDROWIN v2.00 Results ---------------------------
R1
CARBAMATE: >N-C(=O)-O-R3 R1: -H
R2 000592-35-8 R2: -H
000592-35-8 R3: n-Butyl-
Kb hydrolysis at atom # 2: 6.602E-005 L/mol-sec

Total Kb for pH > 8 at 25 deg C : 6.602E-005 L/mol-sec
Kb Half-Life at pH 8: 332.653 years
Kb Half-Life at pH 7: 3326.534 years

HYDROWIN program of EPISuite contains prediction methodology for esters, carbamates, epoxides, halomethanes and alkyl halides. It was developed for the U.S. Environmental Protection Agency and is outlined in the following document:

Mill T, Haag W, Penwell P, Pettit T and Johnson H (1987). "Environmental fate and exposure studies development of a PC-SAR for hydrolysis: esters, alkyl halides and epoxides".  EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International.

Validation

As yet, the QSAR equations in HYDROWIN have not been rigorously tested with an external validation dataset.  Currently, the number of chemicals with evaluated hydrolysis rates is relatively small in number, and the available data have been used to train the QSAR regressions.  HYDROWIN uses linear free energy relationship (LFER) equations.  Similar LFER equations are widely used in the prediction of pKa (Perrin et al. 1981) and in published estimation methods for aqueous hydrolysis (Wolfe and Jeffers, 2000; Wolfe, 1980; Van Hooidonk and Ginjaar, 1967).

Domain

Currently there is no universally accepted definition of model domain.  However, users may wish to consider the possibility that aqueous hydrolysis estimates are less accurate for compounds that have a functional group(s) or other structural features not represented in the training set (see also Section below).

 For example,estersare designated by the formula:

   R1 - C(=O) - O - R2

In the training set, the R2 substituent is an alkyl carbon or an aromatic carbon.  Therefore, any estimate where the R2 is not an alkyl or aromatic carbon would be "outside the estimation domain".  In the training set, the R1 substituent is either an alkyl carbon, an aromatic carbon or a hydrogen.

Assessment for butyl carbamate:

Since the carbamate functional group (-N-C(=O)O-R) is part of the training set, the SoI can be considered to be in domain of the QSAR based model.

Other Estimation Considerations

The underlying program methodology is dependent upon accurate values of Taft steric factors (Es), Taft sigma star constants (Sigma*) and Hammett sigma constants which are scaled to hydrogen fragment (-H) values of zero.  HYDROWIN uses a library of 300 fragments for which corresponding values are available. The fragments and values are identified in HYDROWIN’s on-line user guide help file (Appendix E).  The library consists primarily of common fragments such as linear alkyl, branched alkyl, cyclo-alkyl, halo-alkyls, phenyl, and common oxygen, nitrogen and sulfur derivatives (such as ethers, thioethers, and alkyl-amines).  Realistically, three hundred fragments is only a small fraction of the possible variations of fragments that can exist in chemical structures.

The current HYDROWIN program identifies required fragments from the SMILES notation entry and then matches the actual fragments to the library.  Exact matches are used while inexact matches are assigned a “substitute” that exists in the library.  The process of assigning a substitute has been improved somewhat in this HYDROWIN update; however, this is a very limited fix that requires a much more comprehensive evaluation and updating.  The following example demonstrates the problem:  Consider the fragment CH(OH)C(Cl)(Cl)Cl  (which occurs in the pesticide Trichlorfon) ... the library has fragments such as CH(OH)alkyl and CH2C(Cl)(Cl)Cl, but no combination of both OH and CCl3.  Since both the OH (due to its close proximity) and the Cl3 have significant influence on the steric and sigma star values, an accurate substitute cannot be selected from the existing library because it does not exist anywhere in the library.

The HYDROWIN program could be significantly enhanced by incorporating a methodology to estimate steric and sigma values for fragments that do not currently exist in the fragment library.

In addition, the HYDROWIN program does not consider the effect of ortho-substituents on aromatic rings or the effect of substituents on hetero-aromatic rings (such pyridine or pyrimidine).  This is directly related to lack of experimental hydrolysis rate data.

 Assessment for butyl carbamate:

The following chemical fragments and values are used by the HYDRO program to calculate hydrolysis rate constants. The mono-N-substituted carbamate rates do not require the Taft stearic factor (Es) unlike the esters. Also, the sigma-Meta and sigma-para values apply only to a phenyl ring that is attached directly to the ester or carbamate function. Hence, considering that the SoI is a mono-N-substituted carbamate and does not contain a phenyl ring, it will not require Es or sigma-Meta and sigma-para values for the rate constant calculations.

The below fragment (which is ethyl carbamate equivalent) and corresponding values will be used for the estimation for the SoI.

Fragment	ES	sigma*	sigma-meta	sigma-para
-NH-CO-O-CH2-CH3	-1.50	1.50	0.07	-0.15

Further, as the above fragment, which is ethyl carbamate equivalent and has also been identified as the structurally similar analogue for the SoI, the estimation can be considered to be in domain and reliable.

Conclusions:

Based on the hydrolysis half-lives, the test substance is considered to be resistant to hydrolysis under environmental conditions.

Executive summary:

The hydrolysis rate constant (Kb) and half-lives of the test substance were estimated using the HYDROWIN v.2.00 program (EPISuite v4.1; U.S. EPA. CAS number was used as the input parameter into the tool. The base-catalyzed second-order rate constant (Kb) at pH >8 and 25 °C was estimated to be 6.602E-005 L/mol-sec. The half-lives at pH 8 and 7 were respectively estimated to be 333 and 3327 years indicating stability in water. Therefore, based on the hydrolysis half-lives, the test substance is considered to be resistant to hydrolysis under environmental conditions (US EPA, 2016).

Description of key information

The test substance is considered to be resistant to hydrolysis.

Key value for chemical safety assessment

Half-life for hydrolysis:

3 327 yr

at the temperature of:

25 °C

Additional information

The hydrolysis rate constant (Kb) and half-lives of the test substance were estimated using the HYDROWIN v.2.00 program (EPISuite v4.1). CAS number was used as the input parameter into the tool.The base-catalyzed second-order rate constant (Kb) at pH >8 and 25 °C was estimated to be 6.602E-005 L/mol-sec. The half-lives at pH 8 and 7 were respectively estimated to be 333 and 3327 years indicating stability in water. Therefore, based on the hydrolysis half-lives, the test substance is considered to be resistant to hydrolysis under environmental conditions (US EPA, 2016).