Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
59.42 mg/m³
Most sensitive endpoint:
effect on fertility
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
DNEL value:
740.53 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) = 300*(1/0.38) *6.7/10*7/5 = 740.53 (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 740.53 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
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:
84 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
DNEL value:
4 200 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
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

The substance under registration (CAS 16324-27-9) 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. Six over fourteen registered substances were tested for subchronic toxicity and four of them were tested for chronic toxicity up to two years with no relevant toxic effects. Relevant systemic effects have been reported only in a Rabbit developmental study (Turk A.P., 2000).

The CAS 16470-24-9 (the analogous dihydroxyethylamino derivative, tetrasulphonated sodium salt) was tested for the developmental toxicity in New Zealand White rabbits and Sprague-Dawley rats.

Rabbits were dosed with 100, 400 and 800 mg/kg bw/day by gavage from gestation days 7 – 28, and rats were dosed with 100, 400 and 1000 mg/kg bw/day by gavage from gestation days 6 – 19. The highest dose administered in the rat study (1000 mg/kg bw/day) did not cause toxicity to maternal animals or the developing foetus. In rabbits, the NOELs for maternal and foetotoxicity were 100 mg/kg bw/day, and the NOAEL for teratogenicity was 400 mg/kg bw/day. Exposure to 400 mg/kg bw/day was associated with early delivery in 2 does, abortion in 1 doe, and soft faeces and discoloured stool in general. Mean body weights of all foetuses and male foetuses from does treated with 400 mg/kg bw/day were significantly lower than control. These changes may have been secondary to the maternal toxicity observed in this study and were not considered to be an indication of developmental toxicity.

In the two generation study performed on rat dosed with CAS 16470-24-9 a NOAEL of 300 was set for parental toxicity (Turk A.P., 2000).

Based on the parental toxicity in the rat two generation study, the NOAEL of 300 mg/Kg bw/day has been considered as representative, for hazard assessment.

Representative NOAEL = 300 mg/kg bw/day

The DNELs for inhalation and dermal long-term exposure are derived from the no observed effect level obtained from this oral 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: = NOEL * (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 workers 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 740.53 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). No AF for duration has been added. This results in an overall assessment factor of 12.5.

The DNEL for long-term inhalation exposure, systemic effects is therefore 59.42 mg/m³.

- corrected starting point for the dermal route for workers: = NOEL*10*(7/5) = 4200 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 attached to the section 13) 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). No AF for duration has been added. 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 84 mg/kg bw/d for workers.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.44 mg/m³
Most sensitive endpoint:
effect on fertility
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
DNEL value:
260.87 mg/m³
Explanation for the modification of the dose descriptor starting point:

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 260.87 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
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:
30 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
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
DNEL value:
3 000 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
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:
3 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
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
DNEL value:
300 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
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

The substance under registration (CAS 16324-27-9) 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 24 month chronic toxicity study in the rat, conducted on the acid form of the dihydroxyethylamino disulphonated derivative, no treatment-related clinical symptoms and no signs of systemic toxicity were observed throughout the study. Six over fourteen registered substances were tested for subchronic toxicity and four of them were tested for chronic toxicity up to two years with no relevant toxic effects. Relevant systemic effects have been reported only in a Rabbit developmental study (Turk A.P., 2000).

The developmental toxicity was tested on CAS 16470-24-9 (the analogous dihydroxyethylamino derivative, tetrasulphonated sodium salt) in New Zealand White rabbits and Sprague-Dawley rats.

Rabbits were dosed with 100, 400 and 800 mg/kg bw/day by gavage from gestation days 7 – 28, and rats were dosed with 100, 400 and 1000 mg/kg bw/day by gavage from gestation days 6 – 19. The highest dose administered in the rat study (1000 mg/kg bw/day) did not cause toxicity to maternal animals or the developing foetus. In rabbits, the NOELs for maternal and foetotoxicity were 100 mg/kg bw/day, and the NOAEL for teratogenicity was 400 mg/kg bw/day. Exposure to 400 mg/kg bw/day was associated with early delivery in 2 does, abortion in 1 doe, and soft faeces and discoloured stool in general. Mean body weights of all foetuses and male foetuses from does treated with 400 mg/kg bw/day were significantly lower than control. These changes may have been secondary to the maternal toxicity observed in this study and were not considered to be an indication of developmental toxicity.

In the two generation study performed on rat dosed with CAS 16470-24-9 a NOAEL of 300 was set for parental toxicity.

Based on the parental toxicity in the rat two generation study, the NOAEL of 300 mg/Kg bw/day has been considered as representative, for hazard assessment.

Representative NOAEL = 300 mg/kg bw/day

The DNELs for inhalation and dermal long-term exposure are derived from the no observed effect level obtained from this oral toxicity study with this substance.

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 260.87 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). No AF for duration has been added. The DNEL for long-term inhalation exposure, systemic effects is therefore considered to be 10.44 mg/m³.

- corrected starting point for the dermal route for general population: = NOAEL/0.1 = 3000 mg/kg bw/day (An additional assessment factor (0.1) was used to consider the difference in dermal absorption properties of human and rat skin. The 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 attached to the section 13) 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). No AF for duration has been added.

The resulting DNEL for long-term dermal systemic effects of Stilbene Fluorescent Whitening Agents was 30 mg/kg bw/d for general population.

- corrected starting point for the oral route for general population: = NOAEL = 300 mg/kg bw/day. Subsequently, following assessment factors are taken into account for the final DNEL calculation of systemic oral effects: interspecies differences: human-rat (allometric scaling factor of 4), remaining differences (2.5), intraspecies differences: general population (10). No AF for duration has been added. The resulting DNEL for long-term oral systemic effects of Stilbene Fluorescent Whitening Agents was 3 mg/kg bw/day for general population.