1,4-Benzenediol, 2-(6-oxido-6H-dibenz[c,e][1,2]oxaphosphorin-6-yl)-

Endpoint summary

Description of key information

The aim of this study is to assess the hazardous potential of the substance10-(2, 5-Dihydroxyphenyl)-10H-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO-HQ)with respect to repeated dose toxicity and related reproductive and developmental toxicity effects. The assessment will include expert analysis on the reactivity and possible transformations of the target chemicalas well asin silicopredictions.

Conclusions

       Based on RA prediction to the target chemical using experimental data for its two moieties:

-    NOEL = 105 mg/kg bw/d

-       LOEL = 149 mg/kg bw/d

       It is assumed that DOPO-HQ could elicit low specific target organ (i.e. kidney and/or liver) toxicity effect due to the HQ fragment.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

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:

2019

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:

1. Literature search and expert analysis of the transformations and toxicological effects of DOPO-HQ and its both moieties (DOPO and HQ) have been performed
2. Given the lack of toxicity of the DOPO, it is assumed that the reactivity of DOPO-HQ is due to the HQ fragment which could be transformed to the toxic para-benzoquinone as a result of in vivo metabolism. Based on theoretical expert considerations, it is expected that the toxic effect could be additionally reduced.
a. It is expertly assumed that the formation of quasi-aromatic six-membered hydrogen bond with one of the hydroxyl groups of the HQ fragment will
prevent the extensive oxidation of DOPO-hydroquinone fragment to a toxic para-benzoquinone metabolite.
b. Furthermore, the presence of hydroxyl groups in DOPO-HQ could lead to the excretion of a large part of the target compound via the urine as
glucuronide and sulfate conjugates. This was confirmed by the in vivo rat metabolic simulator available in TIMES.
3. In silico predictions for repeated dose, reproductive and developmental toxicity have been done by Toolbox using the read-across approach. The results confirmed the theoretical analysis based on expert input. Predictions by TIMES QSAR models have been also used for collecting weight of evidences.

Qualifier:

no guideline followed

Guideline:

other: QSAR

Key result

Dose descriptor:

NOEL

Effect level:

105 mg/kg bw/day (nominal)

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other:

Remarks:

QSAR

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

0 other: QSAR

Organ:

kidney

liver

Please see full report

Conclusions:

Conclusions on RDT:
 Based on RA prediction to the target chemical using experimental data for its two moieties:
- NOEL = 105 mg/kg bw/d
- LOEL = 149 mg/kg bw/d
 It is assumed that DOPO-HQ could elicit low specific target organ (i.e. kidney and/or liver) toxicity effect due to the HQ fragment.

Executive summary:

Repeated dose toxicity (RDT) is a hazard property 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.

Table 2. Experimental RDT NOEL/NOAL data for DOPO and HQ

	DOPO		HQ
	Exp. data	Test guideline Duration Data source	Exp. data	Test guideline Duration Data source
NOEL	100 mg/kg	TG 422 42 d Repeated Dose Toxicity HESS database	25 mg/kg	TG NTP 91 d Repeated Dose Toxicity HESS database
LOEL	100 mg/kg	TG 422 42 d Repeated Dose Toxicity HESS database	50 mg/kg	TG 424 91 d ECHA CHEM database

NOEL (RDT, oral, rat, whole body, total)of the target is predicted to be105 mg/kg (Figure 6, see full report).

   LOEL (RDT, oral, rat, whole body, total)of the target is predicted to be149 mg/kg(Figure 7, see full report).

Additional data for DOPO, tested in arepeated dose 90-day oral toxicity in rats,is available in the ECHA CHEM database.Based on the results in the study it was concluded that there is no evidence of specific target organ toxicity and it was defined a no adverse effect level (NOAEL) dose = 1064 mg/kg bw/day.

 

Endpoint conclusion

Endpoint conclusion:

no study available

Dose descriptor:

NOAEL

105 mg/kg bw/day

Organ:

kidney

liver

Justification for classification or non-classification

Findings and NOEL/LOEL do do not justify classification under GHS/CLP