Difluoroacetic acid

Endpoint summary

Description of key information

The substance difluoroacetic acid does not exhibit repeated dose toxicity by oral,inhalation and dermal route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

Remarks:

other: Subchronic;Chronic

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: NTP long-term

Principles of method if other than guideline:

OECD QSAR Toolbox 3.1 prediction; Read Across; 5 nearest analogs; Log Kow discriptor

GLP compliance:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

No data

Frequency of treatment:

No data

Remarks:

Doses / Concentrations:
95.09 mg/kg
Basis:
nominal in water

No. of animals per sex per dose:

No data

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

No data

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

No data

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Dose descriptor:

LOEL

Effect level:

95.1 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: histopathologic changes occurring in the livers of mice

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: "study LOEL","effect LOEL","study NOEL",LOEL,"NOEL calculated",NOEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" or "c" or "d" or "e" or "f" )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and "m" )  and ("n" and "o" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 16 - Oxygen O AND Group 17 - Halogens F AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as PFOA by OECD HPV Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkyl halide AND Carboxylic acid by Organic functional groups

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkyl halide AND Carboxylic acid AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Acid, aliphatic attach [-COOH] AND Alcohol, olefinic attach [-OH] AND Aliphatic Carbon [CH] AND Carbonyl, aliphatic attach [-C(=O)-] AND Fluorine, aliphatic attach [-F] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Alkyl fluoride AND Alkyl halide AND Carbonic acid derivative AND Carboxylic acid AND Carboxylic acid derivative AND Halogen derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.1

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates and isothiocyanates OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Acid anhydrides OR Acylation >> Direct acylation involving a leaving group >> Acyl halide of carboxylic acids OR Acylation >> Direct acylation involving a leaving group >> Carbamates OR Acylation >> Direct acylation involving a leaving group >> N-acylamides OR Acylation >> Direct acylation involving a leaving group >> N-acylated heteroaromatic amines OR Acylation >> Direct acylation involving a leaving group >> N-acylsulphonamides OR Acylation >> Direct acylation involving a leaving group >> Phosphonyl halides OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl halides OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated alkyl or aryl esters OR Acylation >> Ester aminolysis or thiolysis >> Diarylesters OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents OR Michael addition OR Michael addition >> a,b-unsaturated carbonyl compounds OR Michael addition >> a,b-unsaturated carbonyl compounds >> a,b-unsatuarted aldehydes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-carbonyl compounds with polarized double bonds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Nitroalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> N-sulfonylazomethyne compounds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Vinyl sulfonyl compounds OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Activated electrophilic ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Vinyl pyridines OR Michael addition >> Michael-type addition on azoxy compounds OR Michael addition >> Michael-type addition on azoxy compounds >> Azoxy compounds OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone (di)imines OR Nucleophilic addition OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Ketones OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Organic peroxy compounds OR Schiff base formation OR Schiff base formation >> Nucleophilic cycloaddition to diketones OR Schiff base formation >> Nucleophilic cycloaddition to diketones >> Diketones OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives >> Pyrazolones and pyrazolidinones OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Azoxy compounds-forming carbenium ion OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at Nitrogen atom OR SN2 >> Nucleophilic substitution at Nitrogen atom >> N-nitroso compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Activated alkyl esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-activated haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> N-nitroso compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Phosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Sulfonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Thiophosphates OR SN2 >> Nucleophilic substitution on benzylic carbon atom OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> alpha-activated benzyls OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides >> Heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution to the central carbon atom of N-nitroso compounds OR SN2 >> Nucleophilic substitution to the central carbon atom of N-nitroso compounds >> N-nitroso compouns excluding aromatic OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated halogens OR SNAr >> Nucleophilic aromatic substitution on activated halogens >> Activated haloarenes by Protein binding by OASIS v1.1

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halo ethers OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-pyridines by Protein binding by OECD

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals by Groups of elements

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Alkali Earth by Groups of elements

Domain logical expression index: "m"

Similarity boundary:Target: C(=O)(O)C(F)F
Threshold=10%,
Dice(Atom centered fragments)

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.76

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.15

Conclusions:

The oral drinking administration of difluoroacetic acid to mouse, at a dose level of 95.09 mg/kg bw/day, resulted in low observed effect.
Thus the LOEL for repeated dose toxicity study was considered to be 95.09 mg/kg bw/day.

Executive summary:

The oral drinking administration of difluoroacetic acid to mouse, at a dose level of 95.09 mg/kg bw/day, resulted in low observed effect.

Thus the LOEL for repeated dose toxicity study was considered to be 95.09 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

95.09 mg/kg bw/day

Study duration:

subchronic

Species:

mouse

Quality of whole database:

k2 level data as the end point obtained from QSAR estimation

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Data is predicted by QSAR toolbox version 3.1

GLP compliance:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

5 (Weeks/Days)

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Dose descriptor:

LOEL

Effect level:

179.552 other: mg/kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: changed in enzyme activity

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: "effect LOEL"
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

(((("a" or "b" or "c" or "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and "j" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Low (Class I) by Toxic hazard classification by Cramer (original)

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkyl halide AND Carboxylic acid by Organic functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkyl halide AND Carboxylic acid AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkyl fluoride AND Alkyl halide AND Carbonic acid derivative AND Carboxylic acid AND Carboxylic acid derivative AND Halogen derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Highly reactive (GSH) OR Highly reactive (GSH) >> Acrylates (MA) OR Slightly reactive (GSH) OR Slightly reactive (GSH) >> Methacrylates (MA) by Protein binding potency

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.463

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.68

Conclusions:

Repeated dose toxicity LOEL (Lowest observed effect level) of difluoroacetic acid in rat by the inhalation route was found at a dose concentration of 179.551742554 mg/kg/day .

Executive summary:

Repeated dose toxicity LOEL (Lowest observed effect level) of difluoroacetic acid in rat by the inhalation route was found at a dose concentration of 179.551742554 mg/kg/day .On the basis of this LOEL it is concluded that the test substance is not toxic to rat by oral route below the mentioned dose.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

179.551 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

k2 level data as the end point obtained from QSAR estimation

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

WoE Summary of 381-73-7 for repeated dose toxicity

Repeated dose toxicity (Oral):

Based on the various studies available with Klimish rating 2 for the read across substances for CAS: 381-73-7 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows

 

Sr. No	End point	Value	Species	Route	Effects	Remarks
1	LOEL	95.09 mg/ kg bw/ d	Mouse	Oral	histopathologic changes occurring in the livers of mice	Predicted data
2	LOAEL	50 mg/ kg bw/ d	Mouse	Oral	No significant differences in body weight were observed	Data from publication for RA 631-64-1
3	NOEL	5 mg/ kg bw/ d	Rat	Oral	Body weight changes	Data from publication for RA 79-43-6
4	LOEL	50 mg/ kg bw/ d	Rat	Oral	Body weight changes, total serum protein decrease, increase in liver & kidney organ to body weight ratios	Data from publication for RA 79-43-6
5	LOEL	604.17 mg/ kg bw/ d	Rat	Oral	body weight decreased	Predicted data

  

Based on the studies summarized in the above table with oral routes it can be observed that lowest effect value (LOAEL & LOEL) varies from 50 - 604.17 mg/kg bw/d based on the predicted data for the target well as data for read across. Also the predicted value of LOEL is estimated to be 95 mg/Kg bw/d which falls within the range of the LOAEL value and considered to valid prediction. The effects observed on the this doses was listed as follows

 

·        Histopathologic changes occurring in the livers of mice

·        No significant differences in body weight were observed

·        Body weight changes

·        Body weight changes, total serum protein decrease, increase in liver & kidney organ to body weight ratios

·        Body weight decreased

 

Thus based on above discussion it can be concluded that substance CAS: 381-73-7 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the Low effective dose value (LOEL) is 95.09 mg/Kg bw/d thus based on this value it can be concluded that substance difluoroacetic acid is considered to be not toxic to repeated dose below the dose level of 95.09 mg/kg bw/d. On the basis of this LOEL value it is concluded that the test substance is not toxic to rat by the oral route below the mentioned dose. Also there is no known evidence of adverse effect on Human of difluoroacetic acid as well as mechanistic triggers does not classify this substance as toxic substance.

 

Repeated dose toxicity (Inhalation):

Based on the predicted data with Klimish rating 2 for target substance for difluoroacetic acid based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox.

 

The LOEL value 179.55 mg/kg bw/d predicted on rabbit shows effects on the change in enzyme activity

On the basis of this LOEL value it is concluded that the test substance is not toxic via inhalation route for the above mentioned dose.

 

Repeated dose toxicity (Dermal):

The substance is unlikely to have a direct skin contact moreover the physicochemical and toxicological properties suggest low potential of significant rate of absorption through the skin. Further the substance is used as an intermediate in preparation of pharmaceutical chemicals, thereby there is low toxicity potential. This intrinsic property can be extrapolated to repeated dose administration and thus dermal route administration can be waived off.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Repeated dose toxicity LOEL (Lowest observed effect level) of difluoroacetic acid in mouse (B6C3F1) by the oral route was estimated at a dose concentration of 95.09 mg/kg /day.On the basis of this LOEL it is concluded that the test substance is not toxic tomouse (B6C3F1) by oral route below the mentioned dose.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

Repeated dose toxicity LOEL (Lowest observed effect level) of difluoroacetic acid in rat by the inhalation route was found at a dose concentration of 179.551742554 mg/kg/day .On the basis of this LOEL it is concluded that the test substance is not toxic to rat by oral route below the mentioned dose.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

The substance is unlikely to have a direct skin contact moreover the physicochemical and toxicological properties suggest low potential of significant rate of absorption through the skin. Further the substance is used as an intermediate in preparation of chemicals, thereby there is low toxicity potential. This intrinsic property can be extrapolated to repeated dose administration and thus dermal route administration can be waived off

Justification for classification or non-classification

The substance difluoroacetic acid not show repeated dose toxicity effect for oral,dermal and inhalation route and thus will not be considered for further classification.