Benzene-1,3,5-tricarbonyl trichloride

Hydrolysis

Link to relevant study record(s)

Reference

Endpoint:

hydrolysis

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

08-04-2022

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

Justification for type of information:

1. SOFTWARE
Estimation Programme Interface (EPI) Suite programme for Microsoft Windows v4.11
Contact EPISuite:
U.S. Environmental Protection Agency
1200 Pennsylvania Ave.
N.W. (Mail Code 7406M)
Washington, DC 20460

2. MODEL (incl. version number)
HYDROWIN v2.00
September 2010 (model development); November 2012 (model publication)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See QPRF attached: ‘QPRF Title: Substance: benzene-1,3,5-tricarbonyl trichloride using the model HYDROWIN v2.00: for the endpoint: Hydrolysis’ version 1.0; 08 April 2022.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Full details of the method are provided in the attached QMRF named ‘QMRF Title: HYRDOWIN v2.00 for the endpoint: Hydrolysis’ version 1.1 ; date: 30 March 2022.

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See QPRF attached: ‘QPRF Title: Substance: benzene-1,3,5-tricarbonyl trichloride using the model HYDROWIN v2.00: for the endpoint: Hydrolysis’ version 1.0; 08 April 2022.

6. ADEQUACY OF THE RESULT
1) QSAR model is scientifically valid. 2) The substance falls within the applicability domain of the QSAR model. 3) The results are adequate when taken under consideration of REACH Regulation (EC) 1907/2006 in a weight of evidence. The prediction (based upon embedded experimental data) is adequate for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. Specifically, when combined with further information details of which are available. Provision of measured experimental water solubility and/or Partition Coefficient (n-octanol/water) has been determined as not technically possible under guidelines due to the substance being hydrolytically unstable (all pH) with half-life of much less than 12 hours and/or since the substance would decompose/reacts violently during the performance of the test. Therefore, in accordance with the tonnage driven information requirements: the weight of evidence approach to water solubility, partition coefficient and abiotic degradation: hydrolysis has been adopted by the provision of screening and modelled data. This is in conjunction to provision of measured biotic degradation and (eco)toxicological data on the degradant.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Guideline:

other: REACH Guidance on QSARs R.6, May/July 2008

Transformation products:

yes

No.:

#1

No.:

#2

No.:

#3

Details on hydrolysis and appearance of transformation product(s):

- Formation and decline of each transformation product during test: The parent substance will rapidly hydrolyse to the transformation product: benzene-1,3,5-tricarboxylic acid with a t1/2 < 10 minutes at all relevant pH (i.e. pH 4, 7 and 9). The transformation product is hydrolytically stable (t1/2 > 1 year). The transformation product rapidly (biotically) degrades. Refer to ‘Biodegradation’ section for further information.
- Pathways for transformation: Acyl chloride hydrolysis (which may be acid/base catalysed) ; the acid catalysed half-life (t1/2) at pH 7.0 is < 10 minutes. The t1/2 at acid and/or basic pH will be orders of magnitude lower. Note: benzoyl chloride (CAS RN 99-88-4), which has common structural features (acyl chloride and/or aromatic functions) in the same position(s) as the parent substance has an experimental citation: Experimental Half-Lives at 25 deg C (HSDB, 2007; Mabey & Mill, 1978): Benzoyl chloride: 16 seconds. It is upon this experimental information the prediction for the parent substance is based.
- Other: See QPRF attached: ‘QPRF Title: Substance: benzene-1,3,5-tricarbonyl trichloride using the model HYDROWIN v2.00: for the endpoint: Hydrolysis’ version 1.0; 08 April 2022.

Key result

pH:

4

Temp.:

25 °C

DT50:

< 0.01 min

Type:

(pseudo-)first order (= half-life)

Remarks on result:

other: acid catalysed hydrolysis half-life

Key result

pH:

7

Temp.:

25 °C

Hydrolysis rate constant:

> 99.792 d-1

DT50:

<= 10 min

Type:

(pseudo-)first order (= half-life)

Remarks on result:

other: acid catalysed hydrolysis half-life

pH:

9

Temp.:

25 °C

DT50:

< 1 000 min

Type:

(pseudo-)first order (= half-life)

Remarks on result:

other: acid catalysed hydrolysis half-life

Key result

pH:

9

Temp.:

25 °C

DT50:

< 1 min

Type:

(pseudo-)first order (= half-life)

Remarks on result:

other: base catalysed hydrolysis half-life (expert judgement)

Remarks:

See details on results for further information

Details on results:

PATHWAYS OF HYDROLYSIS
- Description of pathways: Acyl chloride hydrolysis (which may be acid/base catalysed) ; the acid catalysed half-life (t1/2) at pH 7.0 is < 10 minutes. The t1/2 at acid and/or basic pH will be orders of magnitude lower. Note: benzoyl chloride (CAS RN 99-88-4), which has common structural features (acyl chloride and/or aromatic functions) in the same position(s) as the parent substance has an experimental citation: Experimental Half-Lives at 25 deg C (HSDB, 2007; Mabey & Mill, 1978): Benzoyl chloride: 16 seconds. It is upon this experimental information the prediction for the parent substance is based.
- Figures of chemical structures attached: Yes. See QPRF attached: ‘QPRF Title: Substance: benzene-1,3,5-tricarbonyl trichloride using the model HYDROWIN v2.00: for the endpoint: Hydrolysis’ version 1.0; 08 April 2022.

- other: The hydrolysis program (HYDROWIN) estimates the rate constant k and half-life of substances at multiple pH-values, at 25°C. The program displays the results at pH 7.0 (acid-catalysed rate constants) and pH 8.0 (base-catalysed rate constants); however its documentation states that the half-life at any other pH may be estimated by moving the decimal point one place to the left or right for each unit of pH. Thus for an acid-catalysed reaction with a half-life of 1 day at pH 7.0, the half-life would be 10 days at pH 8.0, and 2.4 hours at pH 6.0. Based upon this the acid-catalysed half lives are stated for various pH (below):

(i) pH 4.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 0.01 minutes
(ii) pH 5.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 0.1 minutes
(iii) pH 6.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 1 minutes
(iv) pH 7.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 10 minutes (predicted by model programme)
(v) pH 8.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 100 minutes
(vi) pH 9.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 1000 minutes [i.e.< 16.6 hours (or faster)]

However, based upon expert judgement it is noted for acyl chloride hydrolysis under basic conditions (pH > 7.0), the half life should be even faster than the stated acid-catalysed half lives. This is due to a change in mechanism to: base-catalysed nucleophilic addition–elimination via the stronger nucleophile: hydroxide (OH-) directly attacking the acyl group and elimination via SN2 mechanism.

Therefore based upon expert judgement, it can be considered that the reality for hydrolysis in basic conditions, is that the half-life will be orders of magnitude lower than that seen at pH 7.0:

i.e. pH 9.0 (base-catalysed) hydrolysis half-life (t1/2) : < 1 minute (or faster)

Which is considered a suitable limit value. This is also since the acid catalysed half-life (t1/2) at pH 7.0 is itself a conservative estimate, based upon the similar substance experimental half-life - Benzoyl chloride: 16 seconds

There are no differences in transformation products with pH variation. benzene-1,3,5-tricarboxylic acid - transformation product, is generated by either acid/base catalysed acyl chloride hydrolysis, similarly.

1. Defined Endpoint:

QMRF 2. Hydrolysis

QMRF 2.1.a Persistence: Abiotic degradation in water: Hydrolysis

Reference to type of model used and description of results:

The HYDROWIN (Aqueous Hydrolysis Rate Program) for Microsoft Windows v1.42; within Estimation Programs Interface for Microsoft Windows, EPI Suite version 4.11

 

2. Description of results and assessment of reliability of the prediction:

The predicted values are provided within the QPRF attached: ‘QPRF Title: Substance: benzene-1,3,5-tricarbonyl trichloride using the model HYDROWIN v2.00: for the endpoint: Hydrolysis’ version 1.0; 08 April 2022.

Full output of the hydrolysis products is given in the attached QPRF document.

The hydrolysis program (HYDROWIN) estimates the rate constant k and half-life of substances at multiple pH-values, at 25°C. The program displays the results at pH 7.0 (acid-catalysed rate constants) and pH 8.0 (base-catalysed rate constants); however its documentation states that the half-life at any other pH may be estimated by moving the decimal point one place to the left or right for each unit of pH. Thus for an acid-catalysed reaction with a half-life of 1 day at pH 7.0, the half-life would be 10 days at pH 8.0, and 2.4 hours at pH 6.0. Based upon this the acid-catalysed half lives are stated for various pH (below):

Parent substance (benzene-1,3,5-tricarbonyl trichloride) :

(i) pH 4.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 0.01 minutes

(ii) pH 5.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 0.1 minutes

(iii) pH 6.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 1 minutes

(iv) pH 7.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 10 minutes (predicted by model programme)

(v) pH 8.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 100 minutes

(vi) pH 9.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 1000 minutes [i.e.< 16.6 hours (or faster)]

 

However, based upon expert judgement it is noted for acyl chloride hydrolysis under basic conditions (pH > 7.0), the half life should be even faster than the stated acid-catalysed half lives. This is due to a change in mechanism to: base-catalysed nucleophilic addition–elimination via the stronger nucleophile: hydroxide (OH-) directly attacking the acyl group and elimination via SN2 mechanism. Therefore based upon expert judgement, it can be considered that the reality for hydrolysis in basic conditions, is that the half-life will be orders of magnitude lower than that seen at pH 7.0:

 

i.e. pH 9.0 (base-catalysed) hydrolysis half-life (t1/2) : < 1 minute (or faster)

 

Transformation product (benzene-1,3,5-tricarboxylic acid) :

The transformation product is hydrolytically stable (t1/2 > 1 year). Expert judgement. Reference: Lyman W.J. (1990) et al; Handbook of Chemical Property Estimation Methods. Amer. Chem. Soc. pp. 7-4, 7-5.

Note: the transformation product rapidly (biotically) degrades. Refer to ‘Biodegradation’ section for further information.

 

Assessment of the substance within the applicability domains recommended by the developers is documented within the corresponding QMRF ‘QMRF Title: HYRDOWIN v2.00 for the endpoint: Hydrolysis’ version 1.1 ; date: 30 March 2022 – section 5; indicates:

(i) All constituents fall within the Descriptors Domain (general properties, Molecular Weight range).

(ii) The constituent substances have functional groups or features not in the training set of the model and/or for which no fragment constants and correction factors available, per se. However, the constituents are within new chemical class: Acyl Halide for which experimental data is presented and/or for a structural analogue (Benzoyl chloride) that indicates significant hydrolysis potential should be expected and/or a rapid (acid catalysed) hydrolysis half-life (t1/2) at 25ºC and pH 7.0 within 10 minutes or faster is expected. Benzene-1,3,5-tricarboxylic acid degradant, was outside the domain of the model. However, this is expected based on literature and structure to be hydrolytically stable with half life (t1/2) > 1 year. Reference: Lyman W.J. (1990) et al; Handbook of Chemical Property Estimation Methods. Amer. Chem. Soc. pp. 7-4, 7-5.

(iii) There is no overt mechanistic basis for the model other than those described in the relevant chemical classes.

 

3. Uncertainty of the prediction and mechanistic domain:

External validation has not been performed on the model (see QMRF: section 7 for further information). However, the model has been extensively reviewed in the peer reviewed literature. HYDROWIN v2.00 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). HYDROWIN warns the operator when it encounters structures not found in its training set. Minimal testing and reviewing indicates that the method accuracy drops in these situations but may still be acceptable or qualitatively correct (Mill et al, 1987). Model predictivity could be improved by the assignment of additional substances into the training set. Inclusion of additional structural fragments and expansion of sub-structure correction factors and related rules. A full assessment of structural analogues has not been conducted by the applicant. However, based on chemical structure and hydrolysis mechanism (acyl chloride acid hydrolysis) the conclusion of rapid hydrolysis within minutes is scientifically plausible, based upon the acyl chloride hydrolysis mechanisms being widely reported and consistent with information published in the chemical literature. The occurrence of a close structural analogue (Benzoyl chloride, t1/2 = 16 s) cited in the model programme indicates a high degree of confidence. The acyl chloride conclusion of t1/2 < 10 minutes that has been utilized appears highly conservative and that rapid degradation << 1 day at at 25ºC and pH 4.0, 7.0 and 9.0 (i.e. environmentally relevant pH levels) should be expected.

Validity criteria fulfilled:

yes

Conclusions:

The results are adequate for the for the regulatory purpose.

Executive summary:

HYDROWIN v2.00, US EPA (November 2012 (model publication):

Parent substance (benzene-1,3,5-tricarbonyl trichloride) :

(i) pH 4.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 0.01 minutes

(ii) pH 5.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 0.1 minutes

(iii) pH 6.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 1 minutes

(iv) pH 7.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 10 minutes (predicted by model programme)

(v) pH 8.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 100 minutes

(vi) pH 9.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 1000 minutes [i.e.< 16.6 hours (or faster)]

 

However, based upon expert judgement it is noted for acyl chloride hydrolysis under basic conditions (pH > 7.0), the half life should be even faster than the stated acid-catalysed half lives. This is due to a change in mechanism to: base-catalysed nucleophilic addition–elimination via the stronger nucleophile: hydroxide (OH-) directly attacking the acyl group and elimination via SN2 mechanism. Therefore based upon expert judgement, it can be considered that the reality for hydrolysis in basic conditions, is that the half-life will be orders of magnitude lower than that seen at pH 7.0:

 

i.e. pH 9.0 (base-catalysed) hydrolysis half-life (t1/2) : < 1 minute (or faster)

 

The parent substance has very short hydrolytic half-lives (scale: second/minutes) at all relevant neutral pH, ambient temperatures,. Further accelerated in acidic or basic pH conditions by catalytic hydrolysis. They would be considered as fulfilling the criteria for rapid (primary) degradability.

 

Transformation product (benzene-1,3,5-tricarboxylic acid) :

The transformation product is hydrolytically stable (t1/2 > 1 year). Expert judgement. Reference: Lyman W.J. (1990) et al; Handbook of Chemical Property Estimation Methods. Amer. Chem. Soc. pp. 7-4, 7-5.

Note: the transformation product rapidly (biotically) degrades. Refer to ‘Biodegradation’ section for further information.

  

Adequacy of the QSAR:

1) QSAR model is scientifically valid. 2) The substance falls within the applicability domain of the QSAR model. 3) The results are adequate when taken under consideration of REACH Regulation (EC) 1907/2006 in a weight of evidence.The prediction (based upon embedded experimental data) is adequate for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. Specifically, when combined with further informationdetails of which are available.Provision of measured experimental water solubility and/or Partition Coefficient (n-octanol/water) has been determined as not technically possible under guidelines due to the substance being hydrolytically unstable (all pH) with half-life of much less than 12 hours and/or since the substance would decompose/reacts violently during the performance of the test. Therefore, in accordance with the tonnage driven information requirements: the weight of evidence approach to water solubility, partition coefficient and abiotic degradation: hydrolysis has been adopted by the provision of screening and modelled data. This is in conjunction to provision of measured biotic degradation and (eco)toxicological data on the degradant.

Description of key information

Substance half-life for hydrolysis: pH 4: t1/2: ≤ 0.01 minutes; pH 7: t1/2: ≤ 10 minutes; pH 9: t1/2: ≤ 1 minute, at 25°C, 1 atm : via acid/base catalysed acyl chloride hydrolysis, 2022

The parent substance has very short hydrolytic half-lives (scale: second/minutes) at all relevant neutral pH, ambient temperatures. Further accelerated in acidic or basic pH conditions by catalytic hydrolysis. They would be considered as fulfilling the criteria for rapid (primary) degradability. The degradation transformation product is : benzene-1,3,5-tricarboxylic acid with HCl(aq.) and water.

Note: the transformation product rapidly (biotically) degrades. Refer to ‘Biodegradation’ section for further information.

Key value for chemical safety assessment

Half-life for hydrolysis:

10 min

at the temperature of:

25 °C

Additional information

Key data : QSAR – acid (& base) hydrolysis half-lives and/or rate constant(s): HYDROWIN v2.00, US EPA, 2022:

Parent substance (benzene-1,3,5-tricarbonyl trichloride) :

(i) pH 4.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 0.01 minutes

(ii) pH 5.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 0.1 minutes

(iii) pH 6.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 1 minutes

(iv) pH 7.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 10 minutes (predicted by model programme)

(v) pH 8.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 100 minutes

(vi) pH 9.0 (acid-catalysed) hydrolysis half-life (t1/2) : < 1000 minutes [i.e.< 16.6 hours (or faster)]

 

Expert judgement indicates that for acyl chloride hydrolysis under basic conditions (pH > 7.0), the half life should be even faster than the stated acid-catalysed half lives. This is due to a change in mechanism to: base-catalysed nucleophilic addition–elimination via the stronger nucleophile: hydroxide (OH-) directly attacking the acyl group and elimination via SN2 mechanism. Therefore based upon expert judgement, it can be considered that the reality for hydrolysis in basic conditions, is that the half-life will be orders of magnitude lower than that seen at pH 7.0:

 

i.e. pH 9.0 (base-catalysed) hydrolysis half-life (t1/2) : < 1 minute (or faster)

 

The parent substance has very short hydrolytic half-lives (scale: second/minutes) at all relevant neutral pH, ambient temperatures. Further accelerated in acidic or basic pH conditions by catalytic hydrolysis. They would be considered as fulfilling the criteria for rapid (primary) degradability. The degradation transformation product is : benzene-1,3,5-tricarboxylic acid with HCl(aq.) and water.