Sodium 5-(aminosulphonyl)-2-[7-(diethylamino)-2-oxo-2H-1-benzopyran-3-yl]benzoxazolesulphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 516 mg/kg bw when rats were orally exposed with sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate. 

Thus, as per criteria of CLP regulation, sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate can be not classified for reproductive toxicity. 

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

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 using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Name: Sodium 5-(aminosulphonyl)-2-[7-(diethylamino)-2-oxo-2H-1-benzopyran-3-yl]benzoxazolesulphonateCommon Name: Neeliglow Acid Yellow 250SMILES:CCN(CC)c1ccc2C=C(C3(S(=O)(=O)O{-}.[Na]{+})Nc4cc(S(N)(=O)=O)ccc4O3)C(=O)Oc2c1InChI:1S/C20H21N3O8S2.Na/c1-3-23(4-2)13-6-5-12-9-15(19(24)30-18(12)10-13)20(33(27,28)29)22-16-11-14(32(21,25)26)7-8-17(16)31-20;/h5-11,22H,3-4H2,1-2H3,(H2,21,25,26)(H,27,28,29);/q;+1/p-1Molecular Weight: 517.513 g/moleMolecular Formula: C20H19N3O8-S2.Na

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% CMC (carboxymethyl cellulose) in water

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

males: 103 to 106 dayfemales: 55 to 63 days

Frequency of treatment:

Once daily for 7 days per week

Details on study schedule:

not specified

Dose / conc.:

516 mg/kg bw/day

No. of animals per sex per dose:

24

Control animals:

yes, concurrent vehicle

Details on study design:

not specified

Positive control:

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:

not specified

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

Immunological 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:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

516 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

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" or "c" or "d" or "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 Anionic Surfactants by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acid moiety OR Amides OR Esters OR Salt by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "c"

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 Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters by Protein binding by OECD ONLY

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR SN2 OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by Protein binding 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 >> Anhydrides (sulphur analogues of anhydrides)  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides 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 SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "h"

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 AND Michael addition AND Michael addition >> Polarised Alkenes AND Michael addition >> Polarised Alkenes >> Polarised alkene - esters by Protein binding by OECD ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Transition Metals by Groups of elements

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 262 Da

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 685 Da

Conclusions:

NOAEL was estimated to be 516 mg/kg bw when rats were orally exposed with sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate. The NOAEL was estimated to be 516 mg/kg bw when rats were orally exposed with sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate. 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

516 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimisch 2 and from OECD QSAR toolbox

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity - oral

In different studies, sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate has been investigated for reproductive oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate along with the study available on structurally similar read across substance Calcium distearate (CAS no 1592-23-0) and Indigo Carmine (CAS no 860-20-0). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate. The NOAEL was estimated to be 516 mg/kg bw when rats were orally exposed with sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate. 

In another experimental study summarized by Organization for Economic Cooperation and Development (CoCAM 2, 17-19 April 2012) on structurally similar read across substance Calcium distearate (CAS no 1592-23-0), Sprague-Dawley male and female rats were treated with Calcium distearate in the concentration of 0, 250, 500 and 1000 mg/kg bw orally by gavage. No effect on survival of treated male and female rats was observed as compared to control. Alopecia was observed in the vehicle control and treatment groups of both sexes. In males, 2 and animals were observed in 0 and 250 mg/kg bw/day groups, respectively. In females, 1, 1, 1 and 2 animals were observed at 0, 250, 500 and 1000 mg/kg bw/day groups, respectively. Cannibalism, 1 [1 death/140 total fetus (group)], 1 [ 1 death/134 total fetus (group)] and 1 [2 death/137 total fetus (group)] were observed at 0, 250 and 1000 mg/kg bw/day groups, respectively. No effect on body weight of treated rats was observed as compared to control. Statistically significant decrease in food consumption was observed at 2 weeks in 1000 mg/kg bw/day group. Similarly, No effect on reproductive parameters such as Estrus Cycle, mating, fertility and pregnant index of treated rats. Splenomegaly and testicular atrophy were observed in 1 male of the 0 and 1000 mg/kg bw/day groups, respectively. Discoloration of adrenal gland was observed in 1 female of the 250 mg/kg bw/day group. In all reproductive organs in control and high dose groups, the lesion related with the test article was not observed. Adrenocortical necrosis was observed in 1 female of the 250 mg/kg bw/day group. In addition, no effect on viability and body weight of pups on day 0 and 4 were observed. Decrease of food consumption at 2 weeks after administration of 1000 mg/kg bw/day group was considered to be incidental since it was transient during the study period. No effect on organ weight of treated pups was observed as compared to control. Cannibalism was observed in treatment groups, which was occurred commonly in normal parturition and lactation period, because of behavior or environment factor. Testicular atrophy was observed in male at 1000 mg/kg/day group, however, there was no toxic effect of the test article on these organs in histopathology; therefore, this was considered to be a sporadically occurring sign. Discoloration of adrenal gland in female of the 250 mg/kg bw/day group was not considered to be toxicological significance, since no treatment-related change was found in histopathological examination. Therefore, NOAEL was considered to be 1000 mg/kg bw for P and F1 generation when Sprague-Dawley male and female rats were treated with Calcium distearate orally.

Further supported by experimental study given by World Health Organization (WHO) (World Health Organization (WHO) Food Additives Series 6, Eighteenth Report of the Joint FAO/WHO Expert Committee on Food Additives, 1975) and European Food Safety Authority (EFSA) (EFSA Journal 2014;12(7):3768)on structurally similar read across substance Indigo Carmine (CAS no 860-20-0),Wistarmale and female rat were treated withIndigo Carminein the concentration of 0 (vehicle) and 500 mg/kg/day orally by gavage in dietfor 2 years. No effect on survival and growth of treated male and female rats were observed as compared to control in P and F1 rats. Similarly, No effects on reproductive parameters fertility were observed in treated rats as compared to control. In addition, No specific gross pathological and histopathological changes were observed in treated rats. Therefore, NOAEL was considered to be 500 mg/kg/day for P and F1 generation whenWistarmale and female rats treated withIndigo Carmineorally in dietfor 2 years. Therefore,NOAEL was considered to be 500 mg/kg/day for P and F1 generation whenWistarmale and female rats treated withIndigo Carmineorally in dietfor 2 years.

Thus, based on the above study and predictions on sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate and its read across substances, it can be concluded that NOAEL value is 516 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate can be not classified for reproductive toxicity. 

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

Justification for classification or non-classification

Based on the above study and predictions on sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate and its read across substances, it can be concluded that NOAEL value is 516 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, sodium 2-[7-(diethylamino)-2-oxo-2H-chromen-3-yl]-5-sulfamoyl-2,3-dihydro-1,3-benzoxazole-2-sulfonate can be not classified for reproductive toxicity.