E17-194T, (P,P-diethyl, monoester with 1,2 propanediol)_

Endpoint summary

Description of key information

The following modeling approaches and methods will be used in the analysis:

•       OASIS TIMES (AMES, CA, ER, AR) and Catalogic (301C) modeling approach

•       Toolbox 4.2 (TB) for searching of analogues and read-across analysis

•       Available documented data and expert evaluation

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, other

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2018

Reliability:

1 (reliable without restriction)

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:

The following modeling approaches and methods will be used in the analysis:
• OASIS TIMES (AMES, CA, ER, AR) and Catalogic (301C) modeling approach
• Toolbox 4.2 (TB) for searching of analogues and read-across analysis
• Available documented data and expert evaluation

Principles of method if other than guideline:

QSAR modelling

GLP compliance:

no

Key result

Dose descriptor:

other:

Effect level:

0 other: QSAR qualitative data

Based on:

other: QSAR qualitative dat

Remarks:

QSAR qualitative dat

Sex:

not specified

Basis for effect level:

other: QSAR qualitative dat

Remarks on result:

other: QSAR qualitative dat

Key result

Critical effects observed:

not specified

Lowest effective dose / conc.:

0 other: QSAR qualitative data

System:

other: QSAR qualitative data

Organ:

not specified

Conclusions:

• Oral repeated dose administration of some organophosphorus esters could lead to neurotoxic effects associated with inhibition of AChE.
• Phosphinates could interact with AChE, but they are not able to finish the inhibition process including additional reaction of dealkylation (“ageing” mechanism)
due to the lack of second ester group.

• It could be assumed that both constituents of E17-194T will not cause neurotoxicity, i.e. will be non toxic in RDT tests.

Executive summary:

Repeated dose toxicity

Repeated dose toxicity (RDT) is a hazard associated with toxicological effects occurring as a result of repeated daily dosing with/ or exposure to a substance for a specified period up to the expected lifespan of the test species [37]. Currently, there is no existing OASIS model for predicting RDT.

The possible RDT effect of many organophosphorus esters is associated with inducing neurotoxicity by the inhibition of acetylcholinesterase activity [11-13, 38]. In the synaptic cleft OP esters bind to the serine hydroxyl group of AChE and inhibit its activity. The mechanism of AChE inhibition is discussed in sectionIII.3.Toxicological effects of phosphates, phosphonates and phosphinates Mechanistic considerations. As it is mentioned in the same section, the phosphinates are capable to bind covalently with the active site of the enzyme, but cannot continue the inhibition process by aging due to the lack of second ester group (Scheme 3). Moreover, studies with hens showed that the phosphinates protect them from neurotoxic effects because the enzyme was no more available for attack by subsequent doses of neurotoxic organophosphorus compounds (phosphates/phosphonates) [38]. Therefore, it is assumed that both analyzed chemicalswill not cause neurotoxicityafter prolonged exposure.

Experimental repeated dose toxicity data for organophosphorus compounds is searched in literature sources and Toolbox databases.Despite exact RDT data values for phosphinatesarenot found, Johnson reports thatnoneofthescreenedphosphinatesare known to cause delayed neurotoxic effect [38]. 

Oral RDT data (rat) is available for some phosphonates and phosphates in Toolbox (Table 5).However, these chemicals could not be used as analogues of the target chemicals due to different type of activity with respect to AChE inhibition (presence of second ester group in phosphonates and phosphates undergoing “aging” mechanism –Scheme 2).

 

Table 5. RDT data for organophosphorus esters

#	Structure	Experimental RDT data (oral, rat)	Source (Toolbox database)
1.	Dimethyl phosphinate CAS 868-85-9	NOEL = < 25 mg/kg bdwt/d NOEL = 50 mg/kg bdwt/d	Repeated Dose Toxicity HESS
2.	dimethyl methylphosphonate CAS 756-79-6	NOEL = < 250 mg/kg bdwt/d	Repeated Dose Toxicity HESS
3.		NOAEL = 20 mg/kg bw/day NOAEL = 100 mg/kg bw/day;	ECHA Chem
4.	trimethyl phosphate CAS 512-56-1	NOEL = <40 mg/kg bdwt/d	Repeated Dose Toxicity HESS
5	triethyl phosphate CAS 78-40-0	NOAEL = 1000 mg/kg bdwt/d NOAEL = ca. 335 mg/kg bdwt/d	ECHA Chem
6.	dibutyl phosphate CAS 107-66-4	NOEL = 30 mg/kg bw/day	Repeated Dose Toxicity HESS

 

 

Conclusions on RDT:

·     Oral repeated dose administration of some organophosphorus esters could lead to neurotoxic effects associated with inhibition of AChE.

·     Phosphinates could interact with AChE, but they are not able to finish the inhibition process including additional reaction of dealkylation (“ageing” mechanism) due to the lack of second ester group.

·     It could be assumed that both constituents of E17-194T will not cause neurotoxicity, i.e. will benon toxicin RDT tests.

Endpoint conclusion

Study duration:

subchronic

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

No adverse effects are predicted based on the QSAR model.