Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VIII column 2, testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.
Analysis of the particle size distribution revealed that 5.14% of the particles are 10-100 µm (inhalable fraction), 0.03% 4-10 µm (thoracic), and 0.00% <4 µm (respirable). So the thoracic and respirable fraction does not need to be regarded, and only a very minor portion of the substance is inhalable at all. Inhalation of this minimal fraction is excluded by appropriate organisational measures (see respective section). In addition, with a very low vapour pressure of 1.3 x 10E-04 hPa at 20°C, 2.6 x 10E-04 hPa at 25°C and 5.7 x 10E-03 hPa at 50°C, the substance does not need to be regarded as volatile, and inhalation of vapours can be excluded. Last but not least, the substance is a solid, so no aerosols or droplets need to be considered.
In summary, exposure of humans via inhalation is unlikely, so acute inhalation testing can be omitted.

The registrant concludes further that testing is scientifically not necessary and would not reveal any additional information which cannot be derived from other available acute toxicity data, so that testing can be omitted due to animal welfare:
The design of an OECD 403 study (5 mg/l actual concentration of respirable substances) may overestimate the actual exposure, if it would be possible anyway to convert the substance into an inhalable form.
Further, there are no signs of toxicity obvious via the dermal route, and the oral LD50 is 930 mg/kg. There is no study available fulfilling the criteria of an OECD 403 study (and required) for the acute inhalation toxicity of the test item; however, there is other information on acute toxicity in rats available:

Acute toxicity study similar to OECD 401: LD50 =930 mg/kg
Acute toxicity study dermal, acc. OECD 402: LD50 > 2000 mg/kg, LD0 ≥ 2000 mg/kg, no deaths occurred, no signs of systemic toxicity were noted during the observation period.

As outlined in detail in the subchapter “Toxicokinetics”, the absorption rates may be estimated to:
Absorption via oral route: 100%
Absorption via inhalative route: 10%
Absorption via dermal route: 50%

According to OECD guideline 403 (Acute inhalation toxicity), the concentration of respirable particles for limit testing is 5 mg/L over 4 h. Taking into account for rats a standard respiratory volume of 0.2 l/min and average body weight of 250 g (Guidance on information and requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012, ECHA, http://echa.europa.eu/web/guest/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment), a total respiratory volume of 48 litre over 4 h can be assumed. This would result in a total dose of 240 mg per rat, which is equivalent to 960 mg/kg bw.

Taking into account the estimated absorption rates, it can be clearly concluded that any toxicologically relevant amounts can be absorbed. Assuming in a worst-case scenario, although not relevant based on the phys.-chem. properties of the substance, that this total dose will be absorbed to 100%, this dose would correspond to the actually determined oral LD50, and as 960 mg/kg bw corresponds to the limit dose of 5 mg/L over 4 h in an inhalation study, an LC50 equal to the limit dose could be assumed. So even in a worst-case approach, no classification would be triggered. It can be reasonably assumed that an additional acute toxicity test via the inhalation route would reveal an LC50inhalation ≥ 5 mg/l.

So, in summary, it can be reasonably assumed that an additional testing for acute inhalation toxicity would not reveal any further relevant information or trigger classification as acutely toxic via the inhalation route, and consequently, testing can be omitted due to animal welfare.
Cross-referenceopen allclose all
Reason / purpose:
data waiving: supporting information
Remarks:
Particle size distribution
Reference
Endpoint:
particle size distribution (granulometry)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-10-16 - 2017-05-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 110 (Particle Size Distribution / Fibre Length and Diameter Distributions) - Method B: Fibre Length and Diameter Distributions
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of method:
other: fractionated by a 100 µm sieve and tested by scanning electron microscopy (SEM).
Type of particle tested:
primary particle
Type of distribution:
mass based distribution
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
The sample was fractionated by 100 µm sieve and tested by scanning electron microscopy. The fraction < 100 µm was gushed to carbon pads and sputtered with gold.
Mass median aerodynamic diameter:
19.7 µm
Remarks on result:
other: Mass Median Aerodynamic Diameter of the fraction < 100µm, which is 5.17% of the test item (sieve mass fraction <100µm)
Key result
Percentile:
other: 5.17%
Mean:
< 100 µm
Remarks on result:
other: sieve mass fraction
Key result
Percentile:
other: 5.14%
Mean:
>= 10 - <= 100 µm
Remarks on result:
other: sieve mass fraction
Remarks:
inhalable fraction
Key result
Percentile:
other: 0.03%
Mean:
>= 4 - <= 10 µm
Remarks on result:
other: sieve mass fraction
Remarks:
thoracic fraction
Key result
Percentile:
other: 0.00%
Mean:
<= 4 µm
Remarks on result:
other: sieve mass fraction
Remarks:
respirable fraction
Conclusions:
The study was performed according to OECD 110 (method B) under GLP on the substance to be registered itself, the test procedure is well documented and therefore reliability of Klimisch 1 has been assigned. First, the sample was fractionated by a 100 µm sieve, resulting in a sieve mass fraction <100 µm of 5.17%, clearly indicating that the substance has a very low potential to be inhaled. This small portion was further examined by scanning electron microscopy, revealing the following distribution, fraction according their biological relevance (spherical volume): 5.14% 10-100 µm (inhalable), 0.03% 4-10 µm (thoracic), and 0.00% <4 µm (respirable), clearly showing that, if the substance is inhaled at all, it will be practically in total retained in the upper respiratory tract, where it is subject to ciliary cleaning mechanisms.
Executive summary:

The particle size distribution of 2,5-Dimercapto-1,3,4-thiadiazole (DMTD) was determined by scanning electron microscopy after the sample was fractionated by a 100 µm sieve in an OECD 110 (method B) guideline study under GLP. The results are:

 

Sieve Fraction:

weighted sample: 0.996 g

weight fraction <100 µm: 0.0515 g

Sieve mass fraction <100 µm: 5.17%

 

Mass Fraction

Sieve Fraction nominal < 100 µm

Particle Size

Spherical Volume

Cubical Volume

< 4 µm (respirable)

0.00 %

0.00 %

4-10 µm (thoracic)

0.65 %

0.96 %

10-100 µm (inhalable)

99.35 %

99.04 %

>100 µm

0.00 %

0.00 %

Median (diameter)

19.70 µm

19.08 µm

 

The MMAD (Mass Median Aerodynamic Diameter < 100 µm) has a value of 19.70 µm as spherical particles.

Accounting based on the total sample weight

 

Particle Size [µm]

Spherical Volume [%]

Mass Fraction

> 100

94.83

Sieve Fraction

> 100

0.00

Total (> 100 µm)

 

94.83

Sieve Fraction

10-100 (inhalable)

5.14

Sieve Fraction

4-10 (thoracic)

0.03

Sieve Fraction

< 4 (respirable)

0.00

Reason / purpose:
data waiving: supporting information
Remarks:
vapour pressure
Reference
Endpoint:
vapour pressure
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method A.4 (Vapour Pressure)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 104 (Vapour Pressure Curve)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of method:
effusion method: Knudsen cell
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
The test item was tested as received. No further preliminary treatment such as drying or milling was performed. The results given in this report only apply to the tested sample.
Key result
Temp.:
20 °C
Vapour pressure:
0.001 Pa
Remarks on result:
other: extrapolated from the experimental data
Key result
Temp.:
25 °C
Vapour pressure:
0.003 Pa
Remarks on result:
other: extrapolated from the experimental data
Key result
Temp.:
50 °C
Vapour pressure:
0.057 Pa
Remarks on result:
other: extrapolated from the experimental data
Conclusions:
Vapour pressure = 0.0013 Pa at 20°C, 0.0026 Pa at 25°C and 0.057 Pa at 50°C. The GLP study was performed according to OECD TG104 and EU Method A.4 without deviations and therefore reliability of Klimisch 1 has been assigned.
Executive summary:

The vapour pressure of the test substance was determined in a GLP study according to OECD 104 and EU Method A.4 using the effusion method: vapour pressure balance. Vapour pressure was measured in the temperature range of 70 °C to 120 °C and values for 20, 25 and 50 °C were extrapolated from this experimental data:

T / °C   p / hPa
 20  1.3 x 10E-04
 25  2.6 x 10E-04
 50  5.7 x 10E-03
Reason / purpose:
data waiving: supporting information
Remarks:
appearance
Reference
Endpoint:
appearance / physical state / colour
Type of information:
other: observation
Adequacy of study:
key study
Study period:
2017-11-21
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable company statement
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Visual description of the colour (in daylight by an observer with normal colour vision) and the physical state (at 20°C and 1013 hPa)
- Determination of the odour at room temperature and comparison to other substances of characteristic odours
GLP compliance:
no
Physical state at 20°C and 1013 hPa:
solid
Key result
Form:
solid: crystalline
Remarks:
Physical state (at 20 °C and 1013 hPa): solid (crystals)
Colour:
yellow
Odour:
other: not available, not determined out of health and safety reasons
Substance type:
organic
Conclusions:
The determination of the test item's appearance / physical state / colour was determined scientifically reasonably by visual and sensorical inspection. There is no indication given that the results are not reliable. According to the observations made, we certify that this substance can be described as follows:
- Physical state (at 20 °C and 1013 hPa): solid (crystals)
- Colour: yellow
Executive summary:

The visual description of the colour and the physical state (at 20°C and 1013 hPa) resulted in the following: test substance is a yellow solid (crystals).

Reason / purpose:
data waiving: supporting information
Remarks:
absorption rates
Reference

Expert statement: DMTD has a minor potential for bioaccumulation. The relevant absorption rates can be estimated by expert judgement to 100% (oral), 50% (dermal) and 10% (inhalation).

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
10

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion