Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Effect on fertility: via oral route
Endpoint conclusion:
no study available
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

No studies are available with diphosphoric acid, compound with 1,3,5 -triazine-2,4,6 -triamine (1:2). However, reliable data are available for the structrual analogue substance 1,3,5 -triazine-2,4,6 -triamine (CAS 108 -78 -1).

OECD 414 (RL1, rat, oral, RA-CAS 108 -78 -1): NOAEL maternal = 4500 ppm (ca. 400 mg/kg bw/day); NOAEL developmental = 15000 ppm (ca. 1060 mg/kg bw/day)

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 400 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 060 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect up to the highest dose tested
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
A reliable developmental toxicity study according to OECD 414 and GLP is available for the source substance melamine. There were no substance-related findings on the gestational parameters and no signs of developmental toxicity up to and including the highest dose level (15,000 ppm). Especially no indications of teratogenicity were found. The no observed adverse effect level (NOAEL) for the dams is 4500 ppm (about 400 mg/kg body weight/day), but 15,000 ppm (about 1060 mg/kg body weight/day) for the fetal organism. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in reproduction toxicity potential and therefore, no reprotoxicity potential is considered for the target substance as well.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 060 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) and similarities in physico-chemical/ecotoxicological/toxicological properties (refer to analogue justification for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no data available on developmental toxicity of diphosphoric acid, compound with 1,3,5 -triazine-2,4,6 -triamine (CAS 13518 -93 -9). In order to fulfil the standard information requirements set out in Annex VII, 8.3., in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted. In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across). Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

 

A reliable developmental toxicity study according to OECD 414 and GLP is available with the source substance 1,3,5-triazine-2,4,6-triamine (melamine, CAS 108-78-1) (BASF 1996). Melamine was tested for its prenatal toxicity in Wistar rats (BASF 1996). The test substance was administered as a constant homogeneous addition to the food to 23 – 24 pregnant female rats/group at concentrations of 1500, 4500 and 15,000 ppm (136; 400; 1060 mg/kg bw/day) on day 6 through day 16 post coitum. Under the conditions of this study, the administration of melamine to pregnant female rats during organogenesis elicited signs of maternal toxicity at 15,000 ppm. Maternal toxicity was substantiated by reduced food consumption, impairments in body weight/body weight gain, decreased corrected body weight gain and clinical symptoms like haematuria, indrawn flanks and piloerection. Nearly all signs of maternal toxicity proved to be fully reversible after cessation of the test substance administration. The carcass weight and the corrected body weight gain, however, showed still some impairment at terminal sacrifice. There were no substances related findings on the gestational parameters and no signs of developmental toxicity up to and including 15,000 ppm (ca. 1060 mg/kg bw/day, highest dose). Especially no indications of teratogenicity were found. Based on these results a NOAEL for maternal toxicity was set to 4500 ppm (400 mg/kg bw/day) and a NOAEL for developmental toxicity was set to 15,000 ppm (1060 mg/kg bw/day). Based on the above study results with the structural analogue substances melamine (CAS 108-78-1) sufficient evidence is given that the registered substance diphoshoric acid, compound with 1,3,5-triazine-2,4,6-triamine 1:2 (CAS 13518-93-9) is considered not to have developmental toxicity potential.

Mode of Action Analysis / Human Relevance Framework

not applicable

Justification for classification or non-classification

Reliable data from a structural analogue on reproductive toxicity indicates that the registered substance does not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and the available data are therefore conclusive but not sufficient for classification.