Reaction mass of melamine and Nickel, 5,5'-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

58.7 mg/m³

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Value:

1 763.15 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting point was corrected according to Figure R.8 -3 in chapter R.8 in the ECHA guidance document (version 2.1, November 2012). It is assumed that the inhalation absorption in human is similar to the oral absorption in rat. NOAEL(oral, rat) = 424 mg/kg bw/day => NOAEC(corrected, inhalation) = NOAEL(oral, rat) x 1/(0.38 m3/kg bw/day) x 6.7 m3/10 m3 = 747.57 mg/m3

AF for dose response relationship:

1

Justification:

There are no effects up to the limit dose.

AF for differences in duration of exposure:

6

Justification:

Default value (ECHA) for subacute to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.

AF for other interspecies differences:

1

Justification:

In an evaluation by ECETOC in 2003 and 2010 it is considered that routine application of the factor 2.5 as a default factor is scientifically unjustified. The view is supported by data generated by the ERASM project (Batke et al. 2010).

AF for intraspecies differences:

5

Justification:

Default value (ECHA) for workers

AF for the quality of the whole database:

1

Justification:

There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

58.7 mg/m³

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.33 mg/kg bw/day

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assumption, that dermal absorption is not higher than oral absorption, the NOAEL of the oral subacute study is used (ECHA guidance, chapter R.8, R.8.4.1)

AF for dose response relationship:

1

Justification:

There are no effects up to the limit dose.

AF for differences in duration of exposure:

6

Justification:

Default value (ECHA) for subacute to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Defalt value (ECHA) for rat versus human

AF for other interspecies differences:

1

Justification:

In an evaluation by ECETOC in 2003 and 2010 it is considered that routine application of the factor 2.5 as a default factor is scientifically unjustified. The view is supported by data generated by the ERASM project (Batke et al. 2010).

AF for intraspecies differences:

5

Justification:

Default value (ECHA) for workers

AF for the quality of the whole database:

1

Justification:

There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.33 mg/kg bw/day

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Gelbpigment E4GN (Pigment Yellow 150)

(CAS 68511-62-6)

DNELs (worker)

I. Introduction:

Classification (R-phrases) according Regulation (EC) No 1272/2008 Annex VI

No classification (self classification) necessary

II. DNEL systemic

Basis for delineation of the DNELs systemic:

A repeated dose systemic toxicity study in Wistar rats (4 weeks daily administration by gavage) according OECD Guideline 407 is available.

There is no long term study available using the inhalation or dermal route. Thus, as starting point for the calculation, the NOAEL of the subacute oral gavage study has to be taken into account.

Study

Title:

Repeated dose systemic toxicity study in Wistar rats (4 weeks daily administration by gavage)

Administration period: 28 days

Doses: 0, 100, 300 or 1000 mg/kg bw (males + females)

NOAEL, Effects

NOAEL (systemic) = 1000 mg/kg bw (male and female rats)

Effects: Survival was not affected by the treatment with the test substance. Body weight development as well as food and water intake in treated groups was not relevantly affected by the treatment.

Neither hematology nor clinical chemistry gave evidence for treatment-related effects up to 1000 mg/kg.

At clinical observations the only treatment-related finding was that the color of feces was changed (yellowish).

Reference

Schladt L, Gelbpigment E4GN Repeated dose systemic toxicity study in Wistar rats (4 weeks daily administration by gavage). Bayer Pharma AG.

Long-term toxicity – systemic effects (worker)

Long-term inhalation route – systemic effects (worker) using extrapolation factors:

NOAEL (rat) from a subacute oral toxicity study: 1000 mg/kg bw

Correction of the starting point according ECHA Guidance Chapter R.8:

Corrected inhalatory NOAEC = Oral NOAEL (1000 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1

=> NOAEC worker = 1763.15 mg/m³

Factors to be applied: Overall factor 30

Worker DNEL long-term for inhalation exposure: 58.7 mg/m³

Short-term toxicity (inhalation) – systemic effects (worker)

No exceeding factor related to the DNEL for long term exposure is applied.

Long-term dermal route-systemic effects (worker) using extrapolation factors:

Factors to be applied

Overall factor: 120

Worker DNEL long-term for route-systemic:

8.33 mg/kg bw/day

Short-term toxicity (dermal) – systemic effects (worker)

No exceeding factor related to the DNEL for long term exposure is applied.

Therefore:

Worker DNEL short-term for inhalation exposure: 58.7 mg/m³

Worker DNEL short-term for dermal exposure: 8.33 mg/kg bw/day

Toxicity to reproduction:

In a 28 day repeated-dose toxicity study there were no test substance-related toxic changes in organs weights of testes, epididymis, prostate gland, seminal vesicle, vagina, cervix, uterus, ovary/oviduct. No histopathological changes were found in testes, epididymidis, prostate, seminal vesicles with coagulation glands, vagina, cervix, uterus, ovaris/ oviducts and all other examined organs. Therefore the NOAEL for fertility is 1000 mg/kg/day.

In a study according to OECD TG 414 for the maternal and developmental toxicity a NOAEL of 1000 mg/kg/day was determined.

In conclusion, no separate DNEL for toxicity to reproduction is required for Gelbpigment E4GN , as the NOAEL for repeated-dose toxicity and toxicity to reproduction is identical (highest applied dose) and no hazared is identified.

General dust limit:

For insoluble particles, the general threshold value for dust has to be taken into account:

For general dust in Germany the current binding national Occupational Exposure Limit is 10 mg/m³ for inhalable and 3 mg/m³ for respirable dust (TRGS900; http://www.baua.de/cae/servlet/contentblob/666764/publicationFile/55580/TRGS-900.doc).

For the respirable and inhalable fraction of Gelbpigment E4GN the general dust limit should be considered.

III. DNEL local

Basis for delineation of the DNELs local (long and short term toxicity):

Irritation/corrosion

In the key study for skin irritation/corrosion the test substance was slight irritating (erythema score: 1.2 of max. 4; 24, 48, and 72 h). Edema score was not available because exposed skin areas stained in colour of the test substance and only the evaluation of erythema score was possible.

In an in-vitro eye irritation test carried out on a reconstructed human epidermis EST-1000 (CellSystems, St. Katharinen, Germany) Gelbpigment E4GN was not irritating.

In an in-vivo assay according OECD 405 the test item Gelbpigment E4GN revealed a slight erythema (grad 1) 60 min to 24 or 48 hours after application.

Therefore no classification for skin and eye irritation according 67/548/EEC and according GHS is justified.

Sensitization

A modified Local Lymph Node Assay (IMDS) indicated for up to and including a 50% suspension of Gelbpigment E4GN no sensitisation potential.

A classification is therefore not necessary

Result:

For local effects no hazard is identified.

IV: Conclusion (systemic and local effects):

Route of exposure               DNEL; local effect               DNEL; systemic effect

Oral (long term)                             -                                                  -

Oral (short term)                           -                                                  -

Dermal (long term)            No hazard identified               8.33 mg/kg bw/day

Dermal (short term)        No hazard identified               8.33 mg/kg bw/day

Inhalation (long term)        No hazard identified               58.7 mg/m³

Inhalation (short term)        No hazard identified               58.7 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Consumers are not exposed via inhalation and the oral and dermal route as the substance is bound physically in a polymer matrix of an article. Due to the fact that the pigment is embedded in a polymer matrix, consumers are prevented from coming in contact with the embedded pigment. Therefore no relevant exposure via inhalation and the oral and dermal route is expected for consumers.