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Key value for chemical safety assessment

Effects on fertility

Description of key information

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9)Male and female reproductive parameters were unaffected by test material administration. Hence NOAEL was estimated to be 825.00mg/kg bw. When male and female wistar rats were exposed with 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9)orally.Thus, based on the above predictions and experimental study on 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9) and its structurally similar read across substance in a Multigeneration Study performed on two different strain of rats no adverse effects on reproductive and developmental parameter were observed. Thus, comparing this value with the criteria of CLP regulation 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9) cannot be classified as reproductive toxicant.

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 from OECD QSAR toolbox v3.3 and the QMRF report has been attached.
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Prediction was done using OECD QSAR toolbox v3.3, 2017
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of test material (IUPAC name): 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid
- Molecular formula: C17H14N2O8S2
- Molecular weight: 438.4356 g/mol
- Smiles notation: c1cc(cc(c1)N)C(=O)Nc2ccc(c3c2c(cc(c3)S(=O)(=O)O)O)S(=O)(=O)O
-InChl:1S/C17H14N2O8S2/c18-10-3-1-2-9(6-10)17(21)19-13-4-5-15(29(25,26)27)12-7-11(28(22,23)24)8-14(20)16(12)13/h1-8,20H,18H2,(H,19,21)(H,22,23,24)(H,25,26,27)
- Substance type: Organic
Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
40-55 days
Frequency of treatment:
daily, 7 days/week
Details on study schedule:
No data available
Dose / conc.:
825 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20
Control animals:
not specified
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OTHER:
Estrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
825 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
gross pathology
reproductive performance
Remarks on result:
other: No toxic effects were 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:
no effects observed
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:
NOAEL
Generation:
F1
Effect level:
825 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
Remarks on result:
other: overall no effects on developmental parameters
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" or "f" or "g" or "h" )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and "m" )  and ("n" and "o" )  )

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 Anilines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain by DNA binding by OASIS v.1.3

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group AND Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "g"

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: "h"

Referential boundary: The target chemical should be classified as Acid moiety AND Amides AND Anilines (Unhindered) AND Phenol Amines AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "i"

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: "j"

Referential boundary: The target chemical should be classified as AhR binders.Polycyclic aromatic hydrocarbons (PAHs) (3b-3) OR Known precedent reproductive and developmental toxic potential OR NO2-alkyl/NO2-benzene derivatives (8b) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) >> Other non-steroidal estrogen receptor (ER) binding compounds (2b-2) OR Polyhalogenated benzene derivatives (8c) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated carbonyls (Genotox) OR Aromatic diazo (Genotox) OR Dicarboximide (Nongenotox) OR Halogenated benzene (Nongenotox) OR Hydrazine (Genotox) OR Primary aromatic amine,hydroxyl amine and its derived esters (Genotox) OR Quinones (Genotox) OR Structural alert for genotoxic carcinogenicity OR Structural alert for nongenotoxic carcinogenicity OR Structural alerts for both genotoxic and nongenotoxic carcinogenicity OR Substituted n-alkylcarboxylic acids (Nongenotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Very fast by Bioaccumulation - metabolism half-lives ONLY

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.09

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.35

Conclusions:
In reproductive toxicity study, NOAEL was estimated to be 825.00mg/kg bw. When male and female wistar rats were exposed with 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9) orally.
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 for4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9)Male and female reproductive parameters were unaffected by test material administration. Hence NOAEL was estimated to be 825.00mg/kg bw. When male and femalewistar rats were exposed with 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9)

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
825 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)
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 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9)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 rats for 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

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 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9).Male and female reproductive parameters were unaffected by test material administration. Hence NOAEL was estimated to be 825.00mg/kg bw. When male and female wistar rats were exposed with 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9)orally.

Also supported by   experimental study conducted byEuropean Commission(Scientific Committee on Consumer Products (SCCP), OPINION ON Acid Red 33, COLIPA n° C22, 2007 page no -19) on structurally similar read across substance D&C Red 33.(3567-66-6). In a Multigeneration Study, Charles River COBS CD (Sprague Dawley) male and female rats were treated wtih D&C Red 33 in the concentration of 0, 0.25, 2.5, 7.5 and 25.0 mg/kg bw/day orally in diet. One control groups and four test groups (100 males and 100 females) were used. The control and treated rats were maintained on their respective diets for the duration of this generation. F0 parental animals were mated twice (each group 20 males and 20 females), to produce two litters and the F1 parents were mated to produce three litters and the F2 parents were mated once to produce the F3a litters. All the animals were observed for toxicity signs, changes in behaviour and mortality. Body weight and parental food consumption were noted. Reproductive parameters were evaluated to determine male and female fertility indices, gestation anomalies, viability and survival of the pups. Histopathology (14 representative tissues) was performed from control and high dose group from F1 and F3a generation

 No effect on survival of F0, F1 and F2 generation were observed. Discoloration (pink or reddish) of the urine were observed in F0, F1 and F2 treated male and female rats as compared to control. Similarly, no effect on body weight and food consumption of treated F0, F1 and F2 rats were observed as compared to control. No effect on fertility indices, gestation anomalies, viability and survival of the pups were observed in F0, F1 and F2treated rats as compared to control. In addition no effect on histopathology of F0 and F1 treated rats were observed. In F2a generation, 1 pup had exencephaly, spina bifida and great vessel anomalies which were considered an incidental finding. Therefore, NOAEL was considered to be 25 mg/kg bw/day when Charles River COBS CD (Sprague Dawley) male and female rats were treated with D&C Red 33.

Also supported by   experimental study conducted byEFSA(EFSA Journal (2007) 515, 1-28) on structurally similar read across substance RED 2G.(3734-67-6). In Chronic repeated dose oral toxicity study, male and female were treated with RED 2G in the concentration of0 and 100 mg/kg bw/day in feed for 18 weeks and then mated for 10 days. The progeny received the same dietary concentrations from birth and were mated at 16 weeks. The F2 generation finally was also weaned on the same diet. Gross pathology was performed on all the animals.

 No effect on litter size, litter weight, weaning weight and gross pathology of treated F0 and F1 rats were observed Therefore, NOAEL was considered to be 100 mg/kg bw/day for F0 and F1 generation when male and female rats were treated with RED 2G orally in diet for 80 weeks.

  Thus, based on the above predictions and experimental study on 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9) and its structurally similar read across substance in a Multigeneration Study performed on two different strain of rats no adverse effects on reproductive and developmental parameter were observed. Thus, comparing this value with the criteria of CLP regulation 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9) cannot be classified as reproductive toxicant.

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

Thus, comparing this value with the criteria of CLP regulation 4-[(3-aminobenzoyl)amino]-5-hdroxynaphthalene-1,7-disulphonic acid (70239-77-9) cannot be classified as reproductive toxicant.