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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
130 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
1 624.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
NOAEC (human worker) = NOAEL * (1/0.38 m³/kg bw) * 6.7 m³/10 m³* (7/5) = 658*(1/0.38)*6.7/10*7/5 = 1624.2 (0.38 m³/kg bw: default respiratory volume for the rat corresponding to the daily duration of human exposure. For workers a correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. Since worker are exposed 5 days per week and the rats were exposed 7 days per week a factor 7/5 was included.). Thus, the corrected starting point for workers was 1624.2 mg/m³/d for inhalation.
AF for dose response relationship:
1
Justification:
good data about curve dose/response
AF for differences in duration of exposure:
1
Justification:
starting point is from a chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
NAEC Human worker
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
5
Justification:
NAEC Human worker
AF for the quality of the whole database:
1
Justification:
GLP studies compliant with international guideline
AF for remaining uncertainties:
1
Justification:
100 % adsorption for inhalative route for animal and human is assumed
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
184.24 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
other: Corrected NOAEL
Value:
9 212 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Dermal adsorption has been evaluated as negligible, due to the general characteristic of the substance. The substance is in fact a big very polar molecule. Adsorption studies demonstrate that recovery of the substance after dermal application reach a maximum of 2%. At least a factor of 0.1 can be applied to extrapolate from oral to dermal toxicity
AF for dose response relationship:
1
Justification:
good data about curve dose/response
AF for differences in duration of exposure:
1
Justification:
starting point is from a chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
allometric factor rat to man
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Justification:
GLP studies compliant with international guideline
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
carcinogenicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Disodium 4,4'-bis[(4-anilino-6-morpholino-1,3,5-triazin-2-yl) -amino]stilbene-2,2'disulphonate (CAS 16090-02-1) belongs to the category of Stilbene Fluorescent Whitening Agents. This substance and all other members of this category do not show acute toxic effects after oral, inhalation, and dermal administration. They are neither irritant to skin nor eyes, nor genotoxic in-vitro and in-vivo nor sensitizing. In the 28-day subchronic and 24 months chronic toxicity studies in the rat, no treatment-related clinical symptoms and no signs of systemic toxicity were observed throughout the studies.

In a non-GLP study the effect of dietary treatment with 40, 200 or 1000 ppm (ca. 50 mg/Kg bw/day) on reproduction of three different generations of rats was assessed and indicated that up to 1000 ppm the tested material did not indice any adverse effects on either parental generation or their progeny (Industrial Bio-Test Laboratories, Inc., 1973). The reliability of this study cannot be ensured since the study was not audited and additionally no further three-generation studies within the category members were conducted, which would confirm the outcomes. Nevertheless, it was mentioned for completeness sake.

The prenatal toxicity of CAS 32466-46-9 (the free acid form of CAS 16090-02-1) was determined in New Zealand White rabbits and Sprague-Dawley rats (MPI Research Inc., 1998). Oral (gavage) exposure up to 1000 mg/kg bw/day (highest dose tested) had no effect on maternal body weight, body weight gain, food consumption, number of corpora lutea, implantations, live foetuses, preimplantation, postimplantation or resorption rates. Similarly, no treatment-related effects on gravid uterus or adjusted body weight were observed.

In order to perform the hazard assessment, the two-year feeding study in rats with continuous exposure is considered to be most relevant. Since no treatment related adverse effects were observed, the dose level of 791 mg/kg bw/day for females and a dose level of 524 mg/kg bw/day for male is regarded to represent the "no observed adverse effect level" (NOAEL) for the tested substance.

The average NOAEL is therefore 658 mg/kg bw/day

The DNELs for inhalation and dermal long-term exposure are derived from the no observed effect level obtained from the above mentioned oral repeated dose toxicity study. In general, the calculation of DNEL is based on the observed effect level, which has to be modified. To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

- Corrected starting point for the inhalation route for workers: = NOAEL * (1/0.38 m³/kg bw) * 6.7 m³/10 m³* (7/5) (0.38 m³/kg bw): default respiratory volume for the rat corresponding to the daily duration of human exposure. For workers a correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. Since worker are exposed 5 days per week and the rats were exposed 7 days per week a factor 7/5 was included. Thus, the corrected starting point for workers was 1624.2 mg/m³/d for inhalation.

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation: remaining differences (2.5), intraspecies differences: worker (5). This results in an overall assessment factor of 12.5. The DNEL for long-term inhalation exposure, systemic effects is therefore 130 mg/m³.

- Corrected starting point for the dermal route for workers: = NOAEL*10*(7/5) = 1842.4 mg/kg bw/day. An additional assessment factor 10 was used to consider the difference in dermal and oral absorption. Dermal adsorption has been evaluated as negligible, due to the general characteristic of the substance. The substance is in fact a big very polar molecule. Adsorption studies demonstrate that recovery of the substance after dermal application reach a maximum of 2 %. The factor 10 has been chosen in a conservative approach, since not data for all substances are available. Skin adsorption estimations have been performed with DERMWIN for all substances (see Category Justification Report) and it confirms that the behaviour is the same for all members of the category. Since worker are exposed 5 days per week and the rats were exposed 7 days per week a factor 7/5 was included.). Subsequently, following assessment factors are taken into account for the final DNEL calculation of systemic dermal effects: interspecies differences: human-rat (4), remaining differences (2.5), intraspecies differences: worker (5). This results in an overall assessment factor of 50. The resulting DNEL for long-term dermal systemic effects for the Stilbene fluorescent whitening agents was 184.24 mg/kg bw/day for workers.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
572.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
Corrected starting point for the inhalative route for general population: NOAEL * (1/1.15 m³/kg bw/day) (1.15 m³/kg bw/day: default respiratory volume for the rat corresponding to the daily duration of human exposure). Thus, the corrected starting point for the general population was 572.2 mg/m³ for inhalation
AF for dose response relationship:
1
Justification:
good data about curve dose/response
AF for differences in duration of exposure:
1
Justification:
starting point is from a chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
NAEC Human worker
AF for other interspecies differences:
2.5
Justification:
remaining differences
AF for intraspecies differences:
10
Justification:
NAEC Human worker
AF for the quality of the whole database:
1
Justification:
GLP studies compliant with international guideline
AF for remaining uncertainties:
1
Justification:
100 % adsorption for inhalative route for animal and human is assumed
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
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:
DNEL (Derived No Effect Level)
Value:
65.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
other: Corrected NOAEL
Value:
6 580 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Dermal adsorption has been evaluated as negligible, due to the general characteristic of the substance. The substance is in fact a big very polar molecule. Adsorption studies demonstrate that recovery of the substance after dermal application reach a maximum of 2%. At least a factor of 0.1 can be applied to extrapolate from oral to dermal toxicity.
AF for dose response relationship:
1
Justification:
good data about curve dose/response
AF for differences in duration of exposure:
1
Justification:
starting point is from a chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
allometric factor rat to man
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
GLP studies compliant with international guideline
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
carcinogenicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
658 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No extrapolation
AF for dose response relationship:
1
Justification:
good data about curve dose/response
AF for differences in duration of exposure:
1
Justification:
starting point is from a chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
allometric factor rat to man
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
GLP studies compliant with international guideline
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Stilbene Fluorescent Whitening Agents do not show acute toxic effects after oral, inhalation, and dermal administration. They are neither irritant to skin nor eyes, nor genotoxic in-vitro and in-vivo nor sensitizing. In the 28-day subchronic and 24 month chronic toxicity studies in the rat, no treatment-related clinical symptoms and no signs of systemic toxicity were observed throughout the studies.

Since no treatment related adverse effects were observed in the chronic study conducted on the substance to be registered (CAS 16090-02-1), a dose level of 791 mg/kg bw/day for females and a dose level of 524 mg/kg bw/day for male is regarded as representative "no observed adverse effect level" (NOAEL) for this test article. The combined NOAEL is therefore 658 mg/kg bw/day; the DNELs for inhalation and dermal long-term exposure are derived from this starting NOAEL.

In general, the calculation of DNEL is based on the observed effect level, which has to be modified. To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

- Corrected starting point for the inhalation route for general population: NOAEL * (1/1.15 m³/kg bw/day) (1.15 m³/kg bw/day: default respiratory volume for the rat corresponding to the daily duration of human exposure). Thus, the corrected starting point for the general population was 572.2 mg/m³ for inhalation. Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation: remaining differences (2.5), intraspecies differences: general population (10). The DNEL for long-term inhalation exposure, systemic effects is therefore considered to be 23 mg/m³.

- Corrected starting point for the dermal route for general population: = NOAEL/0.1 = 6580 mg/kg bw/day. An additional assessment factor was used to consider the difference in dermal and oral absorption. Dermal adsorption has been evaluated as negligible, due to the general characteristic of the substance. The substance is in fact a big very polar molecule. Adsorption studies demonstrate that recovery of the substance after dermal application reach a maximum of 2 %. The factor 10 has been chosen in a conservative approach, since not data for all substances are available. Skin adsorption estimations have been performed with DERMWIN for all substances (see Category Justification Report) and it confirms that the behaviour is the same for all members of the category. Subsequently, following assessment factors are taken into account for the final DNEL calculation of systemic dermal effects: interspecies differences: human-rat (allometric scaling factor of 4), remaining differences (2.5), intraspecies differences: general population (10). The resulting DNEL for long-term dermal systemic effects of Stilbene Fluorescent Whitening Agents was 65.8 mg/kg bw/day for general population.

- Corrected starting point for the oral route for general population: NOAEL = 658 mg/kg bw/day

Subsequently, following assessment factors are taken into account for the final DNEL calculation of systemic dermal effects: interspecies differences: human-rat (allometric scaling factor of 4), remaining differences (2.5), intraspecies differences: general population (10). The resulting DNEL for long-term oral systemic effects of Stilbene Fluorescent Whitening Agents was 6.6 mg/kg bw/day for general population.