Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study planned
Study period:
2019/2020
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Reactive Yellow 176 (EC 474-870-9)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- Available GLP studies
No GLP study on the substance for the endpoint ‘developmental toxicity / teratogenicity’ is available.
There is the following study from a structural analogue (Tanimoto Index 67.1%) available:
• Combined repeat-dose/developmental screening (OECD 422)
- Available non-GLP studies:
No non-GLP study on the substance for the endpoint ‘developmental toxicity / teratogenicity’ is available.
- Historical human data
No human data suggesting embryotoxicity are available for this substance
- (Q)SAR
It is not possible to reliably determine reproductive toxicity using QSAR
- In vitro methods
There is no validated in-vitro method available to reliably determine developmental toxicity
- Weight of evidence
Insufficient data are available to complete the IUCLID requirements as a weight of evidence approach. The developmental screening study with the structural analogue did not lead to any malformations in the offspring. Likewise, it is not known from existing data with reactive dyes that this kind of substance can cause developmental effects. Thus, it could be argued that the ‘weight of evidence’ based on the class of dyes and known human exposure suggests that the substance is not reprotoxic.
- Grouping and read-across
The following reproductive Annex IX studies for reactive dyes at are available DyStar:
Common name EC no. Tanimoto Index Endpoint OECD
Reactive Yellow F68072 413-090-5 62.5% Teratogenicity 414
One Generation 415
Reactive Blue 225 401-560-2 56.8% Teratogenicity 414
One Generation 415
Reactive Navy H112323 407-420-7 56.1% One generation 415
Reactive Blue 220 291-103-1 50.7% Teratogenicity 414
Reactive Red F01-0481 464-700-1 50.6% Teratogenicity 414
Reactive Black 5 241-164-5 50% Teratogenicity 414
Reactive Blue 19 219-949-9 41.1% Teratogenicity 414
Reactive Blue 21 277-257-2 36.4% Teratogenicity 414

Based on the Tanimoto Index, Reactive Yellow F68072 has the closest structural similarity of the candidates with available studies. Both, Reactive Yellow 176 Sulfato and Reactive Yellow F68072, are azo-dyes, and both have as one reactive group a parabase-ester. Otherwise, the structural similarities of these dyes seem too low, to use this substance for read-across.
As the structural similarity for the other reactive dyes are even lower, these substances are not feasible read-across candidates for Reactive Yellow 176 Sulfato.
- Substance-tailored exposure driven testing: Not applicable
- Approaches in addition to above: Not applicable
- Other reasons: Not applicable

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- According to Column 2 in Annex IX, the study does not need to be conducted if:
• the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented, or
• the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, or
• the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure.
The test substance is neither a genotoxic carcinogen nor a germ cell mutagen. The substance is of low toxicological activity; however, it cannot be proven that no systemic absorption occurs via relevant routes of exposure. Although the very good water solubility, low log Know, high molecular weight and number of H-bond acceptors hint to a low bioavailability, it cannot be excluded from experience from similar reactive dyes that the substance and or its metabolites are absorbed into the body to some extent. In structural similar dyes with a stronger tinctorial effects, discolouration of inner organs and tissues as well as plasma and urine were discovered occasionally.

As none of the above-mentioned exemptions of the standard information requirements are true for Reactive Yellow 176 Sulfato, a developmental toxicity study (OECD 414) has to be conducted for the test substance.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed: OECD 414 including a dose-range finding study
1. Preliminary Oral Prenatal Developmental Toxicity Study in Rats
Test system: S prague-Dawley Rats
Number of animals/group: 6 mated females
Number of groups: 4 (3 treatment groups + 1 control group)
Route of administration: Oral (by gavage)
Treatment period and frequency: Daily from Day 3 to Day 19 post coitum
In vivo observations
Vaginal smears: Daily during pairing
Clinical signs: Daily starting from Day 0 post coitum
Body weight : On Days 0, 3, 6, 9, 12, 15, 18 and 20 post coitum
Post mortem examination :
Macroscopic observations of dams (preserve organs with macroscopic findings)
Gravid uterine weight
Count of corpora lutea
Number of implantation sites
Number of live and dead foetuses
Foetal weight and sex
External examination of all foetuses
GLP Compliance : No


2. Prenatal Developmental Toxicity Study in Rats (OECD 414)
Test system: Sprague-Dawley Rats
Number of animals/group : 25 mated females
Number of groups : 4 (3 treatment groups + 1 control group)
Route of administration : Oral (by gavage)
Treatment period and frequency: Daily from Day 3 to Day 19 post coitum
Formulation analysis : Pre- treatment, during Week 1 and again during last Week of treatment
In vivo observations
Vaginal smears: Daily during pairing
Clinical signs: Daily starting from Day 0 post coitum
Body weight : On Days 0, 3, 6, 9, 12, 15, 18 and 20 post coitum
Food consumption: On Days 3, 6, 9, 12, 15, 18 and 20 post coitum starting from Day 0 post coitum
Post mortem examination :
Dams:
Macroscopic observations of dams
Gravid uterus weight
Count of corpora lutea
Number of implantation sites
Number of live and dead foetuses
Thyroid weight
Blood collection by random selection and in a short timeframe (2 hours in the morning) and hormone determination (T3,T4 and TSH)
Foetuses:
Anogenital distance in all live foetuses
Foetal weight of all live foetuses
External examination of all foetuses (live and dead)
Internal foetal sex determination for dead foetuses and foetuses allocated to the skeletal examination.
Skeletal examination of one half of litters from all groups (single staining)
Soft tissues examination of one half of litters from all groups. Internal sex determination.
Hormone determination : All Dams
Histopathological examination: Thyroid: All Dams
GLP Compliance: Yes

Data source

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
25 June 2018
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
474-870-9
EC Name:
-
Cas Number:
80156-97-4
Molecular formula:
Hill formula: C28H20ClN9Na4O16S5 CAS formula: C28H24ClN9O16S5.4Na
IUPAC Name:
tetrasodium 7-[(E)-2-[2-(carbamoylamino)-4-{[4-chloro-6-({4-[2-(sulfooxy)ethanesulfonyl]phenyl}amino)-1,3,5-triazin-2-yl]amino}phenyl]diazen-1-yl]naphthalene-1,3,6-trisulfonate
Test material form:
solid: particulate/powder
Details on test material:
Reactive Yellow 176 Ester

Test animals

Species:
rat
Strain:
Sprague-Dawley

Results and discussion

Applicant's summary and conclusion