Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
216
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Acute/short-term exposure - systemic effects:

According to ECHA Guidance on information requirements and CSR, chapter R8, a DNEL for acute systemic toxicity should be derived only if an acute systemic toxicity hazard leading to C&L has been identified.

Kerocom F100 has a low acute toxicity as indicated by the LD50 values of > 2000 mg/kg bw determined in rats for oral and dermal exposure, respectively (BASF AG, 2007; BASF SE, 2009). There are no data available concerning acute inhalation toxicity, but inhalation is no relevant exposure route for this substance (substance is a waxy solid at room temperature). Therefore, Kerocom F100 is not subject to classification and labelling concerning acute toxicity and consequently the establishment of DNELs for acute/short-term exposure - systemic effects is not required.

 

Acute/short-term and acute long term exposure - local effects:

Kerocom F100 is a mild skin irritant. Experimental data on respiratory irritation are not available, but inhalation is not an anticipated exposure route for this substance. In the local lymph node assay (LLNA) test Kerocom F100 was skin sensitizing (BASF SE, 2009). 

Below, local effects following acute/short term or long term exposure were assessed qualitatively. A quantitative assessment was not performed because of the following:

- The available skin irritation studies allow only a qualitative assessment of irritation/corrosion following acute exposure.

- There have been several proposals made during the last years how to perform a quantitative assessment for sensitisation based on the LLNA's EC3 value. However, at present there is no common agreement on the assessment factors to be used for a quantitative assessment. Thus, the regulatory acceptance of a proposed DNEL would be highly questionable.

 

Kerocom F100 is classified and labelled with R38 (irritating to skin) according to Directive 67/548/EEC. According to Regulation 1272/2008/EC no classification and labelling is required concerning skin irritation/corrosion.

Kerocom F100 is a skin sensitising agent (R43 according to Directive 67/548/EEC and Cat 1 / H317 according to Regulation 1272/2008/EC). The EC3 value calculated from the result of a LLNA was 1% and indicates a strong skin sensitisation potential (BASF SE, 2009).

Based on these data, Kerocom F100 is allocated to the high hazard category. The operation conditions and risk management measures indicated in the respective IUCLID 5 chapters and the CSR are appropriate and sufficient for controlling the risks.

 

Long term exposure - systemic effects:

In a combined repeated dose toxicity study with reproduction/developmental screening test (enhanced OECD guideline 422) Kerocom F100 was administered to Wistar rats by oral gavage at dose levels of 0, 10, 100, 300 or 1000 mg/kg bw/day (BASF SE, 2010). In order to attain statistical power equivalent to that of a full-scale Generation study (e.g. OECD 416), this study enhanced the guideline recommendations of OECD TG 422 by increasing the group sizes to 22 - 25 (pregnant females). The study was performed in compliance with GLP. The NOAEL for parental animals with regard to systemic toxicity was 100 mg/kg bw/d for males and 300 mg/kg bw/d for femalesbased on adverse clinical pathological findings at next higher doses (increased incidences of higher blood values in the urine of males at 300 mg/kg bw/d; decreased hemoglobin values and red blood cell counts in rats of both sexes, increased ALT activities and globulin values in rats of both sexes, increased total protein, albumin, globulin and cholesterol values in males, and increased incidences of higher blood values in the urine of males at 1000 mg/kg bw/d). 

Kerocom F 100 had no adverse effects on fertility of the F0 parental animals of both sexes, the NOAEL for reproductive performance and fertility was established at 1000 mg/kg bw/day, the highest dose tested.

Macroscopical examination revealed aneurysms of 2 major pericardial blood vessels in pups of all dose groups (10, 100, 300, and 1000 mg/kg bw/d). The ductus arteriosus was the most frequently affected site where aneurysms occurred, thus, this seems to be the most sensitive area to develop aneurysms in this study. Aneurysms were observed in pups from the lower dose groups (10 and 100 mg/kg bw/d), but at a lower incidence compared to the high dose group. Additionally, it must not be overlooked that there was no apparent dose-related increase in the incidence of this lesion between the two lower Kerocom F100 treatment groups (0, 1, 1, 2, 7), representing a 10-fold range in administered dose. This lack of internal consistency in the dose response at dose levels below 300 mg/kg bw/day must be taken into consideration when evaluating these findings.Based on the current limited knowledge, a NOAEL for developmental toxicityin the F1 progeny could not be determined.The LOAEL for developmental toxicity was set to be 10 mg/kg bodyweight/day based on the finding of aneurysms of 2 major pericardial blood vessels in pups of all dose groups (10, 100, 300, and 1000 mg/kg bw/d). This LOAEL is used as the point of departure for the establishment of a dermal DNEL for workers and the general population.

 

- Dermal exposure:

The LOAEL of 10 mg/kg bw/day was established for developmental toxicity and is considered to be the most sensitive dose descriptor and point of departure for DNEL derivation. Taking into account a 10-fold lower dermal absorption in comparison to oral absorption (assumption based on lack of systemic toxicity in acute dermal toxicity study and DERMWIN v2.09 calculation) the calculated LOAEL following dermal application is 100 mg/kg bw /day (10 mg/kg bw /day * 10).

 

The following assessment factors are used for the derivation of the long-term DNEL for dermal exposure: Conversion LOAEL-NOAEL: 3 (lower incidence of aneurysms in lower dose groups compared to the high dose group; no apparent dose-related increase in the incidence of aneurysms between the two lower treatment groups (0, 1, 1, 2, 7), representing a 10-fold range in administered dose; 'flat' dose-response is contraindicative of a treatment-related finding below 300 mg/kg bw/day

); inter-species factor: 4 (allometric scaling), the additional factor of 2.5 is not applied because there is no evidence for species differences in the general mode of action or kinetics; intra-species factor (worker): 3 (according to ECETOC Technical Report No. 86, 2003); exposure duration factor (subacute to chronic): 6.

 

The DNEL is calculated as follows:

DNEL (worker, long-term dermal exposure, systemic effects):100 mg/kg bw/day / (3*4*3*6) = 0.463 mg/kg bw/day=approx. 0.5 mg/kg bw/day

 

- Inhalation exposure:

Inhalation is not a relevant exposure route for this substance (substance is a waxy solid at room temerature). Therefore, inhalation DNELs have not been derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
360
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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

Analogous to the derivation of the DNEL (long-term dermal exposure, systemic effects) for workers the corresponding DNEL for the general population has been derived using the LOAEL of 10 mg/kg bw/day for developmental toxicity and the same assessment factors except an intra-species factor of 5:

 

Long term exposure - systemic effects:

- Dermal exposure:

The LOAEL of 10 mg/kg bw/day was established for developmental toxicity and is considered to be the most sensitive dose descriptor and point of departure for DNEL derivation. Taking into account a 10-fold lower dermal absorption in comparison to oral absorption (assumption based on lack of systemic toxicity in acute dermal toxicity study and DERMWIN v2.09 calculation) the calculated LOAEL following dermal application is 100 mg/kg bw /day (10 mg/kg bw /day * 10).

 

The following assessment factors are used for the derivation of the long-term DNEL for dermal exposure: Conversion LOAEL-NOAEL: 3 (lower incidence of aneurysms in lower dose groups compared to the high dose group; no apparent dose-related increase in the incidence of aneurysms between the two lower treatment groups (0, 1, 1, 2, 7), representing a 10-fold range in administered dose; 'flat' dose-response is contraindicative of a treatment-related finding below 300 mg/kg bw/day

); inter-species factor: 4 (allometric scaling), the additional factor of 2.5 is not applied because there is no evidence for species differences in the general mode of action or kinetics; intra-species factor (general population): 5 (according to ECETOC Technical Report No. 86, 2003); exposure duration factor (subacute to chronic): 6.

 

The DNEL is calculated as follows:

DNEL (general population, long-term dermal exposure, systemic effects): 100 mg/kg bw/day / (3*4*5*6) = 0.278 mg/kg bw/day = approx. 0.3 mg/kg bw/day

 

- Inhalation and oral exposure:

Inhalation and oral uptake are no relevant exposure routes for this substance. Therefore, inhalation and oral DNELs have not been derived.