3',6'-bis(diethylamino)spiro[isobenzofuran-1(3H),9'-[9H]xanthene]-3-one

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction
Since no compound related adverse effects on rats are observed, the no observed adverse effect level (NOAEL) relating to reproductive function for the given test material 3',6'-bis(diethylamino)-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one is estimated to be 720 mg/kg/day via oral route of administration.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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:

Data is predicted by OECD QSAR Toolbox version 3.3. The supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Data is predicted by OECD QSAR Toolbox version 3.3.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of the test material: 3',6'-bis(diethylamino)spiro[isobenzofuran-1(3H),9'-[9H]xanthene]-3-one
- Molecular formula: C28H30N2O3
- Molecular weight: 442.556 g/mol
- Substance type: Organic
- Smiles: C12(c3c(Oc4c1ccc(c4)N(CC)CC)cc(N(CC)CC)cc3)c1c(cccc1)C(O2)=O

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

no

Frequency of treatment:

No data

Remarks:

No data

Control animals:

not specified

Parental animals: Observations and examinations:

Not specified

Oestrous cyclicity (parental animals):

Not specified

Sperm parameters (parental animals):

Not specified

Litter observations:

Not specified

Postmortem examinations (parental animals):

Not specified

Postmortem examinations (offspring):

Not specified

Statistics:

Not specified

Reproductive indices:

Not specified

Offspring viability indices:

Not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

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

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

720 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

clinical signs

reproductive function (sperm measures)

reproductive performance

Remarks on result:

other: not specified

Critical effects observed:

not specified

Reproductive effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "g"

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 >> Azlactones and unsaturated lactone derivatives  OR Michael Addition 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 Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "i"

Similarity boundary:Target: CCN(CC)c1ccc2c(c1)Oc1cc(N(CC)CC)ccc1C21c2ccccc2C(=O)O1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No alert found by rtER Expert System ver.1 - USEPA

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Salicylates by rtER Expert System ver.1 - USEPA

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.643

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.68

Conclusions:

Since no compound related adverse effects on rats are observed, the no observed adverse effect level (NOAEL) relating to reproductive function for the given test material 3',6'-bis(diethylamino)-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one is estimated to be 720 mg/kg/day via oral route of administration.

Executive summary:

The reproductive toxicity of 3',6'-bis(diethylamino)-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one  to rats was estimated using QSAR Toolboox version 3.3. Since no compound related adverse effects on rats are observed, the no observed adverse effect level (NOAEL) relating to reproductive function for the given test material 3',6'-bis(diethylamino)-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one  is estimated to be 720 mg/kg/day via oral route of administration.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

720 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is of K2 reliability and predicted by QSAR toolbox.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction:

The predicted data for target substance 3',6'-bis(diethylamino)-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one (CAS 509-34-2) and the experimental study for its read across substance disodium 3-oxo-3H-spiro[2-benzofuran-1,9'-xanthene]-3',6'-diolate (CAS 518-47-8)has been investigated for potential of toxicity to reproduction via oral route and is presented below as a weight of evidence approach for classification of the target substance:

The reproductive toxicity of 3',6'-bis(diethylamino)-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one  to rats was estimated using QSAR Toolbox version 3.3. Since no compound related adverse effects on rats are observed, the no observed adverse effect level (NOAEL) relating to reproductive function for the given test material 3',6'-bis(diethylamino)-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one  is estimated to be 720 mg/kg/day via oral route of administration.

In a Reproductive/Teratogenic toxicity study, CD Sprague-Dawley female rats were treated with structurally similar substance D&C Yellow no. 8 in the concentration of 0, 100, 500 and 1500 mg/kg body weight/day by oral gavage (Fd Chem. Toxic, Vol. 24, No. 8, pp. 819 823, 1986).Six rats died during the dosing period and at 1500 mg/kg bw/day and Orange discoloration of the urine was observed in all the treated rats as compared to control. Similarly, green discoloration of the amniotic fluid and green colored small intestines were observed at 1500 mg/kg bw/day and green discoloration of the amniotic fluid was observed at 100 and 500 mg/kg bw/day treated rats as compared to control. No effect on Post-implantation loss/dam, Total implantations/dam, Corpora lutea/dam and There were no biologically meaningful or statistically significant differences in the number of litters and Foetal sex of treated rats were observed as compared to control. In addition, No effect on viability of foetuse, number of fetuses with malformations, number of foetuses or litters with developmental variations were observed in any of the treated groups.Slight increase in the number of litters with unossified sternebrae (sternebrae nos 1-6) and rudimentary 14thrib(s) was observed in feotus of 1500 mg/kg bw/day treated rats as compared to control, but the observed effect fell within the ranges of historical control data. Therefore, Reproductive NOAEL was considered to be 1500 mg/kg body weight /day for F0 and F1 generation when CD Sprague-Dawley female rats were treated with D&C Yellow no. 8.

Yet in another study for the same structurally similar substance and from same source (Fd Chem. Toxic, Vol. 24, No. 8, pp. 819 823, 1986), Dutch Belted female Rabbits were treated with D&C YELLOW NO. 8 in the concentration of 0, 30, 100 and 250 mg/kg body weight/day by oral gavage.One rabbits died each in 30 and 250 mg/kg bw/day including control. One rabbit aborted on day 28 of gestation at 250 mg/kg bw/day as compared to control. Pneumonia was observed in three rabbit which were died. Orange discoloration of the urine was observed in all the treated rabbits between days 7 and 28 of gestation as compared to control. No effect on body weight and body weight gain and No effect on Post-implantation loss/dam, Total implantations/dam and Corpora lutea/dam were observed in treated rabbits as compared to control. Similarly, there were no biologically meaningful or statistically significant differences in the number of litters, Foetal sex and gross pathological changes were observed in treated rabbits as compared to control. In addition, No effect on viability of foetus, foetal body weight and sex of foetus were observed as compared to control. At 30 and 100 mg/kg be/day, malformations were observed in two foetuses from two litters. However, these values fell within the ranges of historical control data. There were no biologically meaningful or statistically significant differences in number of fetuses with malformations,number of foetuses or litters with developmental variations were observed in foetuses of any of the treated groups. Therefore, Reproductive NOAEL was considered to be 250 mg/kg body weight /day for F0 and F1 generation when Dutch Belted female rabbits were treated with D&C YELLOW NO. 8 orally by gavage from day 6 to 27 of gestation.

Based on the above mentioned studies for target substance and to its read across substance and by comparing these with the CLP criteria, it can be concluded that no adverse effects on reproductive performance was observed. Therefore by applying weight of evidence approach the substance3',6'-bis(diethylamino)-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one is considered to be not classified as Reproductive toxic chemical.

Justification for classification or non-classification

On the basis of evidence from above studies in, it can be presumed that there is no potential of the targert substance to be harmful to rat for reproductive toxictiy.