Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 900 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEL
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

For Uvinul A Plus, several studies addressing repeated dose toxicity are available:

In an oral (feed) 90 day subchronic toxicity study in rats according to OECD TG 408, the no observed effect level (NOAEL) was set at 15000 ppm (equal to 1249 mg/kg bw/day in males or 1452 mg/kg bw/d in females).

In a two-generation reproduction study in rats (oral, feed) according to OECD TG 416, a NOAEL was set at 100 mg/kg bw/day for general parental toxicity, a NOAEL for fertility and reproductive performance was set at 300 mg/kg bw/day, and a NOAEL for developmental toxicity was set at 100 mg/kg bw/day.

In a developmental toxicity study according to OECD TG 414 in rats (oral, gavage), the maternal NOAEL was determined at 200 mg/kg bw/day, whereas the NOAEL for prenatal developmental toxicity was set 1000 mg/kg body weight/day.

 

Data from the listed studies were found suitable for deviation of respective DNELs.

The systemic parental NOAEL of the two-generation reproduction study was chosen as the point of departure for derivation of the dermal long term systemic DNEL by route to route extrapolation.

 

Route to route extrapolation: oral – dermal:

0.15% is chosen for percutaneous penetration and absorption in humans, based on:

% absorbance in vivo rat study * ( % absorbance human in vitro study/ % absorbance rat in vitro study)

3% * (0.5% / 10%) = 0.15 %

Bioavailability of Uvinul A Plus in rats after oral application was determined to be 26% and 45% for male and female animals, respectively.

 

For the worker, the following DNELs has been derived:

The systemic parental NOAEL of the two-generation reproduction study was set at 100 mg/kg bw/d Uvinul A Plus for males and females.

 

For derivation of the long-term systemic dermal DNEL, the oral NOAEL was converted into a corrected dermal NOAEL of 17.3 g/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008).

 

NOAEL corrected dermal = 100*(26/0.15) = 17333 mg/kg bw/d

 

Based on the availability of a sufficient toxicity dataset, the default assessment factors (acc. to ECHA GD R8) have been modified into substance specific assessment factors (AF), considering the intrinsic hazard properties of the registered substance. The following findings form the basis of the rationale for the substance specific AF:

 

  • In a subchronic feeding study in rats (acc. to OECD TG 408) no test substance related effects have been observed up to the highest dose tested (1250-1450 mg/kg bw/d test substance in crystalline form).
  • In a gavage developmental toxicity study in rats (acc. to OECD TG 414) adverse effects have been observed only in the high dose group (1000 mg/kg bw/d test substance in a crystalline form) consisting of decreased food consumption, decreased body weight gain and clinical observations, i.e. salivation)
  • In a 2-generation feeding study in rats (acc. to OECD TG 416), the test substance has been administered in a melt form. Adverse parental effects became evident at 1000 and 300 mg/kg bw/d and consisted of decreased food consumption, decreased body weight/gains and clinical observation such as reduced nutritional and impaired general state. Besides a certain form of kidney toxicity (-> formation of alpha 2µ globuline) noted only in male F1 rats, therefore being considered species specific and without any relevance for humans, no test substance related organ toxicity has been observed. Subsequent irregularities in the reproductive performance and adverse effects in the offspring have been observed and assessed to be secondary to maternal stress. 

The following substance specific assessment factors (AF) were applied:

·       allometric scaling = 1 

·       remaining differences = 1

·       intraspecies = 3 

 

Derivation from the standard AF for allometric scaling and remaining differences:

Feeding of the crystalline form in the subchronic feeding study exceeding the limit dose of 1000 mg/kg bw/d did not result in any test substance related adverse effects.

As seen in the developmental toxicity study, administration at 1000 mg/kg bw/d via gavage resulted in unspecific adverse systemic effects being considered to be related to bad-tasting/ irritating properties of the test substance.

In line, mostly unspecific systemic effects related to palatability issues have been observed in parental animals of the 2-generation feeding study. Differences in palatability compared to the subchronic feeding study might be explained by the alternate physical state of the test substance used (crystalline versus melt). The observed rat specific kidney toxicity and an oral bioavailability study prove sufficient oral uptake of the test compound investigated.

  • Since findings described above are based mainly on palatability issues, they would not depend on a systemic toxic parent compound/metabolite being excreted dependent of caloric demand. Therefore, use of AF >1 for allometric scaling is not considered necessary based on the nature of effects observed.
  • Since no human relevant organ specific toxicity has been observed and palatability is considered to be the cause of adverse effects with no relevance for workers, no additional AF covering toxicodynamic differences (i.e. remaining differences) between rats and humans are considered necessary.   
  • Major findings in the listed studies are specifically triggered by the route of exposure, i.e. oral. Since oral exposure is not considered relevant, the relevance of these findings are doubtful for workers (ECHA GD R8).

Derivation from the standard AF for intraspecies variability:

The nature of adverse effects observed mainly based on palatability issues were not considered to depend on human intraspecies variations in toxicokinetics or toxicodynamics. Furthermore, palatability triggered effects would not represent a concern for workers as pointed out above. Although the observed effects would not require an additional AF, an AF of 3 has been included to cover for remaining uncertainties within a controlled subpopulation, i.e. healthy workers.

 

The following default assessment factors (AF) were applied:

·       exposure duration = 2 (subchronic to chronic);

·       quality of whole database = 1 (based on validity of studies performed).

The multiplicatory principle of AF has been maintained, although there were no substantial adverse effects of relevance for the worker. Therefore the overall assessment factor would be as follows:

AF = 1 x 1 x 3 x 2 x 1 = 6

Consequently, the dermal long-term systemic DNEL derived was 2.9 g/kg bw/d for the worker.

Taken together with the conservative choice of the NOAEL as point of departure, it is assumed that this provides a sufficient degree of conservatism.

 

For derivation of a long-term systemic inhalation DNEL, 10 mg/m3 has been defined . This value is based on the general dust limit value (TRGS 900, established by AGS (Ausschuß für Gefahrstoffe), published by the German BMAS (Bundesministerium für Arbeit und Soziales")), since Uvinul A Plus does not pose any intrinsic hazard and has a low water solubility.

 

No further DNELs were derived, since Uvinul A does not pose any hazard, leading to a non-classification according to the criteria laid down under 67/548/ECC and CLP.

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

Based on the present toxicological data, the substance does not pose any hazard, leading to a non-classification according to the criteria laid down under 67/548/ECC and CLP. Since all relevant uses are outside the scope of REACH and inside the scope of the Cosmetics Directive 76/768/EEC, no DNELS have been derived for the general population according to "Guidance on information requirements and chemical safety assessment (Chapter R8).