Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:

Data source

Referenceopen allclose all

Reference Type:
other company data
Title:
Unnamed
Report date:
2010
Reference Type:
publication
Title:
A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study.
Author:
Janer G, Hakkert BC, Piersma AH, Vermeire T, Slob W
Year:
2007
Bibliographic source:
Reproductive Toxicology, 24(1), 103-113.
Reference Type:
publication
Title:
A simple dermal absorption model: Derivation and application.
Author:
Berge, W. ten
Year:
2009
Bibliographic source:
Chemosphere 75, 14401445.

Materials and methods

Test material

Constituent 1
Reference substance name:
melam
IUPAC Name:
melam

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

The 90-day toxicity study did not indicate any adverse effects on reproductive organs or tissues. No indications for reproductive toxicity are also obtained from the two developmental toxicity studies with rats and mice. Melam is not genotoxic in two Ames-tests, in two in vitro chromosome aberration assay and in an in vivo micronucleus test.

Justification according to T. Tiemersma and Wil ten Berge:

"Compounds with the structure of melamine and melam are not mentioned in the list of reproductive toxic substances in the last REACH regulations 1272/2008 and 790/2009. In one case the triazine-structure is part of the molecule, but the molecular moieties attached to it, are causing clearly the reproductive toxic properties of the substance.

Janer et al (2007) carried out a retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic study. They considered 47 reproductive toxic substances and 75 nonreproductive toxic substances, for which a 2 generation reproduction study was available. Incidentally a NOAEL of more than a factor of 10 smaller was found for the 2 generation reproductive study in comparison with the subchronic study, but this was caused by wide dose spacing in the former. Finally Janer et al. (2007) concluded, that the difference between the NOAEL of a 2 generation reproductive study is generally a factor of 2 smaller than the NOAEL of a subchronic study.

This conclusion is in line with the NOAELs of the developmental toxicity (teratogenicity) studies in mice and rats. In both developmental toxicity studies (mice and rats) the NOAEL appeared to be 500 mg/kg bw/day. Developmental toxicity is one of the studied endpoints in a two generation reproductive toxicity study.

Let us assume, that the NOAEL of the 2 generation reproduction study is half the NOAEL of the subchronic study, that is 1000/2 = 500 mg/kg bw/day. The proposed default interspecies assessment factor for extrapolation from rat to man is 10 and the proposed default human intraspecies assessment factor is 5 (REACH guidance 8) for workers and 10 for consumers. This means that a dose level of 10 mg/kg bw/day should be considered as a safe dose level for workers in order to prevent reproductive toxic effects and is mentioned the DNEL (Derived No Effect Level) for reproductive toxic effects in workers. The DNEL for reproductive toxic effects for consumers is 5 mg/kg bw/day. The DNEL for reproductive toxic effects (10 mg/kg bw/day) of workers is larger than the maximum worker exposure (1.43 mg/kg bw/day). The DNEL for reproductive toxic effects (5 mg/kg bw/day) is 8 orders of magnitude larger than the estimated consumer exposure.

Conclusion:

A 2 generation reproductive toxicity study of melam can be exempted based on the following arguments:

- The substance was demonstrated to lack any genotoxic effects for point mutations in vitro.

- The substance was demonstrated to lack any genotoxic effects by chromosomal aberrations in vitro.

- Because melam fails to induce any genotoxic effects via different mode of actions in vitro, melam cannot be a germ cell mutagen in vivo.

- The NOAEL in a 28-day and 90-day repeated dose toxicity study by ingestion appeared to be 1000 mg/kg. This means that melam is non-toxic.

- Exposure via inhalation at the maximum OEL of 10 mg/m3 results into a maximum inhaled dose of 1.4 mg/kg bw/day for workers. The major part of the inhaled dose will be absorbed by secondary ingestion. The mucous escalator of the respiratory tract transports the melam dust to the mouth and is subsequently swallowed. Only a very small part might be retained in the alveoli and systemically absorbed directly into the blood.

- Dermal exposure is estimated to be negligible. According to the QSAR of ten Berge (2009) the aqueous permeation coefficient is estimated to be 2.5E-5 cm/hour. The water solubility is assumed to be 10 mg/litre. If the full body skin (18000 cm2) is covered with melam dust for 24 hours, the maximum dermal systemic absorption is estimated to be (24*18000*10/1000*2.5E-5=) 0.108 mg/day. This amount is small compared to the inhaled amount of melam of 100 mg at the OEL of 10 mg/m3 and a daily inhalation volume during working time of 10 m3.

References:

- Janer G, Hakkert BC, Piersma AH, Vermeire T, Slob W, 2007. A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study, Reproductive Toxicology, 24(1), 103-113."

- Berge, W. ten, 2009. A simple dermal absorption model: Derivation and application. Chemosphere 75, 14401445."