Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.576 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 28 -day study in rats was selected as the most representative starting dose based on: study duration; presence of adverse effects, which were completely reversible during a 2 -week recovery period; type of observations and parameters taken into account to identify effect levels.

 

In comparison, in studies of toxicity to reproduction to assess teratogenic effects in rats, animals were dosed for a shorter period, i.e. from day 6 to 15 of pregnancy; observations were mainly focused on reproductive parameters and few details on the general toxicity of the substance were reported; in the preliminary assay, a NOAEL of 20 mg/kg (17 mg/kg a.i.) and LOAEL of 80 mg/kg (68 mg/kg a.i.) were identified based on maternal toxicity and a NOAEL of 80 mg/kg (68 mg/kg a.i.) for teratogenicity; in the main assay, lower doses were tested and no adverse effects were recorded (tested doses: 1.5, 5, 15 mg/kg).

 

Starting from an oral dose of 35 mg/kg (NOAEL) as a.i. corresponding to 40 mg/kg as test material, a corrected value is obtained, based on: 8-h breathing volume of rat (0.38 m3/kg) and 8-h breathing volume of human (6.7 m3/kg in general population and 10 m3/kg in worker); days per week of exposure in experimental animals (7 d/w) and in humans (5 d/w in workers).

No experimental data on absorption via oral and inhalation route was available. Worst case assumption for absorption was: 50 % orally and 100 % by inhalation.

 

NOAEC = ((35 mg/kg bw/day : 0.38 m3/kg) × (6.7 m3: 10 m3)) × (7 d/w : 5 d/w) × 0.5 = 43.2 mg/m3

AF for dose response relationship:
1
Justification:
Modified descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
6
Justification:
extrapolation from subacute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
implicitly included in the corrected starting point
AF for other interspecies differences:
2.5
Justification:
toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part)
AF for intraspecies differences:
5
Justification:
workers
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
no significative remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Absorption by dermal route is expected to be low based on:

- low toxicity by dermal route compared to oral route as suggested by a LD50 > 2000 mg/kg by dermal route and LD50 between 50 and 300 mg/kg by oral route;

- water solubility of 25.22 g/l and logPow of -0.3993, i.e. above 10 g/l and below 0 respectively, thus limiting the penetration into the stratum corneum;

- presence of heterocyclic ammonium ions in the molecule that may bind to skin components.

However, the substance is classified as skin sensitising (cat. 1B of the CLP Regulation EC 1272/2008). Skin sensitisation is a non-threshold endpoint, thus a repeated exposure to test substance may cause hypersensitivity reactions even in case of low absorption potential.

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

Additional information - workers

In general, the calculation of a DNEL is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. If there is no basis for setting a DNEL or DMEL for a given human health endpoint, i.e. due to the lack of quantitative dose-response information, but there exists toxicity data of a qualitative nature, a qualitative risk assessement is performed. This kind of situation typically occurs with data on irritation/corrosion, sensitisation, acute toxicity, mutagenicity, and carcinogenicity.

INHALATION ROUTE

Systemic effects after long term exposure

The substance is a powder and particles have a mass-median diameter of 35 µm and ca. 97 % of particles is below 100 µm size. The fraction of respirable particles, which may enter the alveolar region and become systemically available upon absorption, is less than 2 %. Despite the low potential for systemic exposure via inhalation, a DNEL is derived.

The starting point to derive a long term DNEL for inhalation route was a NOAEC of 43.2 mg/m3derived from a NOAEL of 35 mg/kg bw/d (highest tested dose in a repeated dose toxicity study in rats by oral route) properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human (worker) breathing volume. Worst case for absorption rate was assumed, namely 50 % by oral route and 100 % by inhalation. Assessment factors were used to derive the DNEL:

- remaining interspecies differences 2.5

- intraspecies differences 5, for workers

- differences in duration of exposure 6, because the starting value resulted from a subacute study.

Systemic effects after acute exposure

No acute inhalation toxicity study was available. However, as the inhaled substance may likely enter the gastrointestinal tract via clearance mechanism and the substance is classified for acute oral toxicity (cat. 3 of the CLP Regulation), a systemic acute effect upon inhalation may occur and a medium hazard is expected.

Local effects after acute and long term exposure

The substance is a powder and particles have a mass-median diameter of 35 µm. Based on the particle size distribution, 97 % of particles has a diameter below 100 µm. Mucous lining the respiratory tract may be exposed to the substance and may enter the gastrointestinal tract as a consequence of clearance mechanisms.

As the substance causes eye damage and causes damage to the gastrointestinal tract in studies by oral route, an effect on mucous of respiratory and gastrointestinal tracts upon inhalation may occur and a medium hazard is expected.

DERMAL ROUTE

Molecular structure of the substance, physicochemical properties and findings in studies by dermal route are indicative of a low potential for absorption by dermal route.

Systemic effects after long term and acute exposure

Systemic effects upon dermal exposure were assessed in a skin sensitisation study. The substance resulted as sensitising, with positive responses to challenge in 50 % of tested animals and no threshold for either induction or elicitation, based on available data.

Based on the potency categorisation for guinea pig maximisation test, reported in ECHA guidance R.8, the substance is considered a moderate sensitiser and a medium hazard is expected.

Local effects after long term and acute exposure

No long term studies upon dermal exposure were available. As no local effects were noted in skin irritation studies and in an acute toxicity test by dermal route, the substance resulted as non irritant and no local hazard is expected.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
86.3 µg/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):
150
Dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
13 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 28 -day study in rats was selected as the most representative starting dose based on: study duration; presence of adverse effects, which were completely reversible during a 2 -week recovery period; type of observations and parameters taken into account to identify effect levels.

 

In comparison, in studies on toxicity to reproduction to assess teratogenic effects in rats, animals were dosed for a shorter period, i.e. from day 6 to 15 of pregnancy; observations were mainly focused on reproductive parameters and few details on the general toxicity of the substance were reported; in the preliminary assay, a NOAEL of 20 mg/kg (17 mg/kg a.i.) and LOAEL of 80 mg/kg (68 mg/kg a.i.) were identified based on maternal toxicity and a NOAEL of 80 mg/kg (68 mg/kg a.i.) for teratogenicity; in the main assay, lower doses were tested and no adverse effects were recorded (tested doses: 1.5, 5, 15 mg/kg).

 

Starting from an oral dose of 35 mg/kg (NOAEL) as a.i. corresponding to 40 mg/kg as test material, a corrected value is obtained, based on 24-h breathing volume of rat (1.15 m3/kg). Exposure conditions of experimental animals and humans (general population) are the same, i.e. 7 days per week.

No data on absorption via oral and inhalation route was available. Worst case assumption for absorption was: 50 % orally and 100 % by inhalation.

NOAEC = ((35 mg/kg bw/day : 1.35 m3/kg) × 0.5 = 13 mg/m3

AF for dose response relationship:
1
Justification:
Modified descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
6
Justification:
extrapolation from subacute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
implicitly included in the corrected starting point
AF for other interspecies differences:
2.5
Justification:
toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part)
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
no significative remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
DNEL (Derived No Effect Level)
Value:
58.3 µg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No extrapolation.

AF for dose response relationship:
1
Justification:
NOAEL clearly identified
AF for differences in duration of exposure:
6
Justification:
extrapolation from subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default value
AF for other interspecies differences:
2.5
Justification:
toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
no significative remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

In general, the calculation of a DNEL is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. If there is no basis for setting a DNEL or DMEL for a given human health endpoint, i.e. due to the lack of quantitative dose-response information, but there exists toxicity data of a qualitative nature, a qualitative risk assessement is performed. This kind of situation typically occurs with data on irritation/corrosion, sensitisation, acute toxicity, mutagenicity, and carcinogenicity.

INHALATION ROUTE

Systemic effects after long term exposure

The substance is a powder and particles have a mass-median diameter of 35 µm and ca. 97 % of particles is below 100 µm size. The fraction of respirable particles, which may enter the alveolar region and become systemically available upon absorption, is less than 2 %. Despite the low potential for systemic exposure via inhalation, a DNEL is derived.

The starting point to derive a long term DNEL for inhalation route was a NOAEC of 13 mg/m3derived from a NOAEL of 35 mg/kg bw/d (highest tested dose in a repeated dose toxicity study in rats by oral route) properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human (worker) breathing volume. Worst case for absorption rate was assumed, namely 50 % by oral route and 100 % by inhalation. Assessment factors were used to derive the DNEL:

- remaining interspecies differences 2.5

- intraspecies differences 10, for general population

- differences in duration of exposure 6, because the starting value resulted from a subacute study.

Systemic effects after acute exposure

No acute inhalation toxicity study was available. However, as the inhaled substance may likely enter the gastrointestinal tract via clearance mechanism and the substance is classified for acute oral toxicity (cat. 3 of the CLP Regulation), a systemic acute effect upon inhalation may occur and a medium hazard is expected.

Local effects after acute and long term exposure

The substance is a powder and particles have a mass-median diameter of 35 µm. Based on the particle size distribution, 97 % of particles has a diameter below 100 µm. Mucous lining the respiratory tract may be exposed to the substance and may enter the gastrointestinal tract as a consequence of clearance mechanisms.

As the substance causes eye damage and causes damage to the gastrointestinal tract in studies by oral route, an effect on mucous of respiratory and gastrointestinal tracts upon inhalation may occur and a medium hazard is expected.

DERMAL ROUTE

Molecular structure of the substance, physicochemical properties and findings in studies by dermal route are indicative of a low potential for absorption by dermal route.

Systemic effects after long term and acute exposure

Systemic effects upon dermal exposure were assessed in a skin sensitisation study. The substance resulted as sensitising, with positive responses to challenge in 50 % of tested animals and no threshold for either induction or elicitation, based on available data.

Based on the potency categorisation for guinea pig maximisation test, reported in ECHA guidance R.8, the substance is considered a moderate sensitiser and a medium hazard is expected.

Local effects after long term and acute exposure

No long term studies upon dermal exposure were available. As no local effects were noted in skin irritation studies and in an acute toxicity test by dermal route, the substance resulted as non irritant and no local hazard is expected.

ORAL ROUTE

Systemic effects after long term exposure

The starting point to derive a DNEL for oral long-term exposure was a NOAEL of 35 mg/kg bw/d obtained from a repeated dose toxicity study. This was the highest tested dose, at which systemic effects were found to be completely reversible at the end of the recovery period. Assessment factors were used to derive DNEL:

- differences in duration of exposure 6, because the starting value resulted from a subacute study

- interspecies differences 4, from rat to human

- remaining differences 2.5

- intraspecies differences 10, for general population.

Systemic effects after acute exposure

The substance is classified for acute toxicity in cat. 3 of the CLP Regulation (EC 1272/2008), thus it is considered as moderately toxic and a medium hazard is expected.