Disodium 8-hydroxynaphthalene-1,6-disulphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL was estimated to be 306 mg/kg bw when rats were orally exposed with N-(phenylsulphonyl)benzenesulphonamide.  

Thus, as per criteria of CLP regulation, Disodium 8-hydroxynaphthalene-1,6-disulphonate 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 3.4 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 3.4

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Name: Disodium 8-hydroxynaphthalene-1,6-disulphonate
SMILES:Oc1cc(S(=O)(=O)O{-}.[Na]{+})cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
InChI:1S/C10H8O7S2.2Na/c11-8-5-7(18(12,13)14)4-6-2-1-3-9(10(6)8)19(15,16)17;;/h1-5,11H,(H,12,13,14)(H,15,16,17);;/q;2*+1/p-2
Mol. formula: C10H6Na2O7S2
Molecular Weight: 348.2624 g/mole

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Remarks on MMAD:

not specified

Vehicle:

corn oil

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Approx 46 days

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

306 mg/kg bw/day

No. of animals per sex per dose:

12

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:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

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:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

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

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" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and "p" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Naphthalene sulfonic acids, condensates by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Substituted Phenols by Protein binding by OASIS v1.4

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid moiety AND Phenols AND Salt by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Substituted Phenols by Protein binding by OASIS v1.4

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 >> Michael-type addition to quinoid structures  >> Hydroxylated Phenols OR Michael addition OR Michael addition >> Michael addition on polarised Alkenes OR Michael addition >> Michael addition on polarised Alkenes >> Polarised Alkenes - sulfones  OR No alert found OR Radical reactions OR Radical reactions >> ROS Generation OR Radical reactions >> ROS Generation >> Sterically Hindered Piperidine Derivatives OR Schiff base formation OR Schiff base formation >> Direct acting Schiff base formers OR Schiff base formation >> Direct acting Schiff base formers >> 1,2-Dicarbonyls and 1,3-Dicarbonyls  OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aromatic carbonyl compounds OR SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Phosphonates OR SN2 >> Protein and/or DNA alkylation OR SN2 >> Protein and/or DNA alkylation >> Dialkyl Alkylphosphonates OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.4

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) >> 4-alkylphenol-like derivatives (2b-3) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) >> Other non-steroidal estrogen receptor (ER) binding compounds (2b-2) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aryl AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Biphenyl by Organic Functional groups

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Aryl AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Sulfide, poly by Organic Functional groups

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Phenols (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 212 Da

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 764 Da

Conclusions:

NOAEL was estimated to be 306 mg/kg bw when rats were orally exposed with N-(phenylsulphonyl)benzenesulphonamide.

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 Disodium 8-hydroxynaphthalene-1,6-disulphonate. The NOAEL was estimated to be 306 mg/kg bw when rats were orally exposed with N-(phenylsulphonyl)benzenesulphonamide.  

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

306 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:

In different studies, Disodium 8-hydroxynaphthalene-1,6-disulphonate has been investigated for reproductive 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 mice and rats for Disodium 8-hydroxynaphthalene-1,6-disulphonate along with the study available on structurally similar read across substance FD & C RED NO. 40 (disodium salt of 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulph ophenyl)azo]-2-naphthalene sulphonic acid.) (CAS no 25956-17-6), Sunset Yellow FCF or FD&C Yellow No. 6. (CAS no 2783-94-0) and Green S (CAS no 3087-16-9). 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 Disodium 8-hydroxynaphthalene-1,6-disulphonate. The NOAEL was estimated to be 306 mg/kg bw when rats were orally exposed with N-(phenylsulphonyl)benzenesulphonamide.  

In another experimental study conducted by Collins et al (Food and cosmetics toxicology, Vol. 18. pp 561 to 568, 1980) on structurally similar read across FD & C RED NO. 40 (disodium salt of 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulph ophenyl)azo]-2-naphthalene sulphonic acid.) (CAS no 25956-17-6), Osborne-Mendel female rats were treated with FD & C RED NO. 40 in the concentration of 260.2 mg/kg body weight /day in distilled water by oral drinking water. No external signs of toxicity and animals were appeared healthy and behaved normally in treated groups as compared to control. No effects on maternal weight gain and significant decrease in water consumption were observed in treated female rats as compared to control. No significant effects on numbers of corpora lutea, implantations, early and late deaths and viable foetuses per litter or on the percentage of preimplantation loss were observed in treated group as compared to control. Similarly, no significant effect on percentage of early resorptions and percentage of females with more than one and with more than two resorptions were observed in treated rats as compared to control. In addition, No effect on live or dead fetuses and mean fetal body weight and percentage of males and females per treatment group were observed as compared to control. Increase in number of runts was observed in litters, but no external variations were observed in litters of treated dams as compared to control. No effect on Crown-rump length and Sex distribution were observed in litters of treated dams as compared to control. Slight increase in number of affected litters, number of bipartite sternebrae and reduced ossification of the parietal bone were observed in litters of treated dams as compared to control. But, the observed increases did not appear to be dose-related. Therefore, NOAEL was considered to be 260.2mg/kg body weight /day for F0 and F1 generation when Osborne-Mendel female rats were treated with FD & C RED NO. 40. orally in Drinking water for 19 days.    

Further supported by experimental study conducted by Collins et al (Food and cosmetics toxicology, Vol. 18. pp 561 to 568, 1980) on structurally similar read across FD & C RED NO. 40 (disodium salt of 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulph ophenyl)azo]-2-naphthalene sulphonic acid.) (CAS no 25956-17-6), In a Embryotoxicity and teratogenicity study, Osborne-Mendelfemale rats were treated with FD & C RED NO. 40 in the concentration of 0, 7.5, 15, 30, 100 and 200 mg/kg body weight /day in distilled water by oral gavage. No external signs of toxicity and animals were appeared healthy and behaved normally in treated groups as compared to control. No effects on maternal weight gain and water consumption were observed in treated female rats as compared to control. No significant effects on numbers of corpora lutea, implantations, early and late deaths and viable fetuses per litter or on the percentage of preimplantation loss were observed in treated group as compared to control. Slightly increase in percentage of early resorptions was observed in 7.5 and 15 mg/kg bw/day but this response were appeared to be the result of sporadic occurrences. One litter was totally resorbed at 100 mg/kg bw/day. But, the percentage of females with more than one and with more than two resorptions showed no dose-related correlation as compared to control. In addition, No effect on live or dead fetuses and mean fetal body weight and percentage of males and females per treatment group were observed as compared to control. Increased in number of runts were observed at 7.5, 15, 100 and 200 mg/kg bw/day treated dams, No compound-related external variations were observed in litters of treated dams as compared to control. Slightly decrease in males and females Crown-rump length were observed but were not significantly significant with increasing dose level. No effect on percentage of males and females per treatment group were observed as compared to control. Similarly, increase in fetuses with hydroureters were observed but affected fetuses were well distributed among the litters and slight, but not significant, increase in the percentage of fetuses with soft-tissue variations were observed at 200 mg/kg bw/day, slight increase in the number of internal haemorrhages at 15 mg/kg bw/day were observed as compared to control. No dose-related increase in the average number of variations per litter or in the average number of fetuses with one or more soft-tissue variations were observed in litters of treated rats as compared to control. Slight increases in number of bipartite sternebrae, number of malaligned sternebrae and number of animals with fourteenth rib buds were observed in litters of 7.5, 30 and 200 mg/kg bw/day treated rats as compared to control. The observed increases did not appear to be dose-related. Therefore, NOAEL was considered to be 200 mg/kg body weight /day for F0 and F1 generation when Osborne-Mendelfemale rats were treated with FD & C RED NO. 40 orally by gavage for 19 days.

Again supported by experimental study conducted by Tanaka et al (Toxicology and industrial health,Vol 12,No.1,page no.69-79.1996) on structurally similar read across Sunset Yellow FCF or FD&C Yellow No. 6. (CAS no 2783-94-0), 60 Crj: CD-1 male and female mice (10/sex/group) were treated Sunset Yellow FCF in the concentration of 300, 600, and 1200 mg/kg bw/day the control groups (20 mice, 10/sex) were given basal diets (Nihon Clea, CE-2) for 17 weeks. During experiment adverse effects observed as dam having underdeveloped mammary glands. The survival indices at PND 0 showed viability indices at birth. The survivals were significantly reduced in the middle-dose group (600 mg/kg bw/day) of each sex. And on other side the average body weight of male and female mice showed no significant adverse effects from the treatment during the preconception period, and the average body weight of dams showed no significant adverse effects during the gestation or lactation periods. No effects on food consumption and movement activity of exploratory behavior in either sex at eight weeks of age. Therefore, NOAEL for maternal and developmental toxicity was considered to be 300 mg/kg bw/day whereas LOAEL was considered to be 600 mg/kg bw/day in Crj: CD-1 strain mouse when Sunset Yellow FCF was administered orally by diet.

Further supported by experimental study conducted by Clode et al (Food Chemical Toxicology. Vol. 25, No. 12, pp. 995-997, 1987) on structurally similar read across Green S (CAS no 3087-16-9), Water female rats treated with Green S in the concentration of 0, 250, 500 and 1000 mg/kg/day orally by gavage. No effect was observed on body weight of treated rats as compared to control. Similarly, No effect were observed on number of corpora lutea, implantation sites, Pre-implantation losses, early resorptions, late resorptions and post-implantation losses of treated female rats as compared to control. No effect was observed on fetal weight as compared to control. In addition, slightly green colouring in the gastro-intestinal tract and the placental tissue were observed in treated female rats. Green colouring of the gastro-intestinal tract and placenta were observed because Green S is largely unabsorbed. Statistically significant increase in fetuses with mucus in tracea were observed in 250, 500 and 1000 mg/kg/day and Ossification of proximal phalanges and fourth metacarpals of Skeletal tissue were observed in 500 and 1000 mg/kg/day treated fetoses as compared to control. These findings were observed at all dose levels and the incidence was not dose related. Despite this association with treatment, the nature of the finding does not indicate an adverse effect. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when Water female rats treated with Green S orally by gavage for 19 days.

Above studies are again supported by experimental study conducted by Moorhouse et al (Food Chem. Toxic. Vol. 25, No. 12, pp. 985-993, 1987) on structurally similar read across Green S (CAS no 3087-16-9), Wistar male and female rats treated with Green S in the concentration of 0, 50, 500 and 1000 mg/kg body weight/day orally in diet. In Parental generation, No effect were observed on survival, body weight, Food consumption, compound intake and water consumption of treated male and female rats as compared to control. Signs of respiratory distress, faeces, fur and extremities of all treated animals became impregnated or coated with the colouring were observed in treated and control. In addition, Significant decrease were observed in absolute stomach and empty caecum weight and increased in relative kidney weight in male and increased in absolute and relative empty and full caecum, spleen, and gonads weight in female and full caecum weight in male were observed at 1000 mg/kg body weight/day treated rats. Occasional focal inflammatory lesions were observed in the liver, heart, kidney and stomach in 1000 mg/kg bw/day and presence of colouring in wall of the uterus as a distinct ring around the placenta, and appeared to be confined to the amniotic membrane were observed in 500 and 1000 mg/kg bw/day treated female rats as compared to control. Significant increased in isolated foci or as a more widespread multifocal lesion associated with slight parenchymal necrosis and a portal inflammatory infiltrate of liver in female rats and statistically significantly increase in number of submucosal granulocytes and a slight vacuolation of overlying epithelium of stomach in male rats were observed at 1000 mg/kg bw/day as compared to control. In F1, F2 and F3 generation, Significantly decrease in number of live foetuses were observed in P generation and Slightly earlier incisors were observed in F1, F2 and F3 generation at 500 and 1000 mg/kg bw/day and in F2 and F3 generation at 50 mg/kg bw/day. This was associated with a large number of late resorptions in four animals. Significantly increased pups weight was observed in P and F1 generation at 50 mg/kg bw/day as compared to control. Both changes in F0 and F1 stages were associated with slightly smaller litters. Similarly, Minor variations in the degree of skeletal ossification were observed in alizarin-stained preparations, there were no differences that could be associated with treatment. Therefore, NOAEL was considered to be 500 mg/kg body weight/day for P, F1, F2 and F3 generation when Wistar male and female rats were treated with Green S orally in diet for 229 days.

Thus, based on the above study and predictions on Disodium 8-hydroxynaphthalene-1,6-disulphonate and its read across substances, it can be concluded that NOAEL value is 306 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, Disodium 8-hydroxynaphthalene-1,6-disulphonate 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 Disodium 8-hydroxynaphthalene-1,6-disulphonate and its read across substances, it can be concluded that NOAEL value is 306 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, Disodium 8-hydroxynaphthalene-1,6-disulphonate can be not classified for reproductive toxicity.