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Key value for chemical safety assessment

Effects on fertility

Description of key information

A reproductive/developmental screening study (OECD 422, GLP compliant) was conducted in rats to investigate the potential adverse effect on reproduction of one analogue substance at doses 0, 30, 150 and 750 mg/ kg bw/day (by gavage). The study covered observation on reproductive performance, including mating, fertility, gestation, parturition data and litter responses. Under the conditions of this study, no test substance-related effects were observed on reproductive performance at any dosage level. Based on these results, 750 mg/kg bw/day was considered to be the NOAEL for reproductive toxicity.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance Direct Red 254 TEA salt (CAS No 64683-40-5 / EC 265-016-4) is defined as a mono-constituent substance with cations triethanolammonium.
The available toxicological data on this substance are insufficient to fulfil the data requirements for a REACH Annex VIII dossier.
In order to prevent unnecessary animal testing, the occurring data gaps on toxicity studies might be filled by applying read-across from the similar substance Direct Red 254 sodium salt (CAS No 6300-50-1 / EC 228-589-1). Both salts of Direct Red 254 are synthetized using the same raw materials and following the same manufacturing process.
The only difference between the query structure Direct Red 254 TEA salt (CAS 64683-40-5) and Direct Red 254 sodium salt (CAS 6300-50-1) is the counter ion. CAS 6300-50-1 is the result of a neutralization with NaOH, whilst the alkaline agent used in CAS No. 64683-40-5 is triethanolamine.
Both substances are identical in relation to the anionic components.

The read-across is based on the hypothesis that source and target substances have similar toxicological properties because both molecules have the following similarities: a) Identical raw materials; b) Identical manufacturing process; c) Identical anionic structure composition; d) Identical degradation products by reductive cleavage; e) Both have affinity to the same type of substrates/molecules. The substances are able to be adsorbed on the same type of substance, e.g. polysaccharides (cellulose), polyphenols (lignin) and proteins; f) Both substances have similar physicochemical properties

In summary, it is considered that both substances have the same mode of action with regard to the following endpoints: Acute Oral toxicity, Skin irritation, Eye irritation, Skin sensitisation, Mutagenicity and Repeated dose and reproduction / developmental (screening).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Read across is possible provided that there is no impact of impurities on the toxicological properties of the target and source chemicals. For both, impurities are comparable.
The composition and impurities of the target and source substances are shown in table 1 of the attached document to this record.

3. ANALOGUE APPROACH JUSTIFICATION

The target chemical Direct Red 254 TEA salt (CAS No 64683-40-5) is a mono-constituent substance, with cations triethanolammonium.
Direct Red 254 Sodium salt (CAS No 6300-50-1) is assumed as source chemical since it is identical to the target chemical Direct Red 254 TEA salt (CAS No 64683-40-5) in respect of the different chemical anionic component but varies in the cation. The physicochemical properties of both substances are nearly identical. No experimental data on absorption, distribution and excretion is available for the source and target substances and their hydrolysis products. The toxicokinetics assessment is based on the physicochemical properties and the available toxicological data of the substances.
The source chemical CAS No 6300-50-1 is ionisable and is assumed that will be dissociated in aqueous media or in biological fluids to the anionic component and free Na+ cation. Sodium ion is a naturally occurring cation in the body with a blood plasma concentration of 140 mmol/L. It is excreted with the urine and does not cause any toxic effects when administered in low concentrations.
In analogy to the source chemical also CAS No 64683-40-5 (target chemical) is expected to be dissociated shortly after absorption and the cation TEA+ is also assumed to be readily available in the body. The TEA+ cation can be assimilated to triethanolamine (CAS No 102-71-6).
Base on that the only difference between the target structure (CAS No 64683-40-5) and the source structure (CAS 6300-50-1) is the counter ion, and the influence to the human health toxicity, irritation and / or sensitisation effects due to the presence of TEA+ in the target chemical CAS No 64683-40-5 is not expected. Consequently, read-across to the source chemical CAS No 6300-50-1 is regarded as feasible.
A broad and more detailed explanation is included in the attached document in section 13 of this dossier.

4. DATA MATRIX
Two data matrix are included in the attached document in section 13 of this dossier: Matrix 1 (Toxicity data on the source and target substance) and Matrix 2 (Main potential metabolites data)
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
Key result
Dose descriptor:
NOEL
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Dose descriptor:
NOEL
Generation:
F1
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: offspring development
Key result
Reproductive effects observed:
no
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

Description of key information

A reproductive/developmental screening study (OECD 422, GLP compliant) was conducted in rats to investigate the potential adverse effect on reproduction of one analogue substance at doses 0, 30, 150 and 750 mg/ kg bw/day (by gavage). The study covered observation on reproductive performance, including mating, fertility, gestation, parturition data and litter responses. Under the conditions of this study, no test substance-related effects were observed on reproductive performance at any dosage level. Based on these results, 750 mg/kg bw/day was considered to be the NOAEL for reproductive toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

A reproductive/developmental screening study (OECD 422, GLP compliant) was conducted in rats to investigate the potential adverse effect on reproduction of one analogue substance. No adverse effects on reproductive/ developmental parameters were noted at doses up to 750 mg/kg bw/day in parental animals. Also, there were no effects on the general physical condition of the offsprings at any dose.

The substance therefore does not qualify for classification for these endpoints according to CLP (Regulation 1272/2008/EC).

Additional information