Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because skin contact in production and/or use is not likely
the study does not need to be conducted because inhalation of the substance is likely
other:
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Key value taken from published data. 
Boiling point at 101 325 Pa:
-29.8 °C

Six references are available for inspection. The reference values closely matches the registrants experience of the substance and is considered suitable for use, on the basis of a weight of evidence approach.

Reason / purpose for cross-reference:
data waiving: supporting information
Reference

Experimental data for acute Oral and inhalation toxicity, although not performed according to most current standards, showed a low acute toxicity at the highest achievable dose levels.

Endpoint conclusion:
no adverse effect observed
Quality of whole database:
No specific methods and details of the test conditions were provided, and this study could be waived in accordance with Annex VII, Section 8.5.1 which states that:
8.5.1. By oral route - The study need not be conducted if a study on acute toxicity by the inhalation route (8.5.2) is available.
The result of acute oral toxicity test is reported at > 1000 mg/kg. Because it is reported as the maximum feasible dose, with no mortality observed no classification is proposed for oral toxicity. In addition, this route of exposure is not anticipated.
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
493 510 mg/m³
Quality of whole database:
The literature data provides information for a number of mammalian species, and is considered appropriate for use in the scope of a weight of evidence approach. Although exposures are for 30 minutes only, the report indicates that there were no effects at the highest concentration tested. One additional literature source reported similar effects following a 30 min-exposure and 4hr or 6 hr-exposure to 800 000 ppm, i.e. no mortality observed, but anesthetic/narcotic effects at the highest concentrations (70 to 80% v/v).

Review of the EU legislation does not provide for conversion from 30 min LC50 exposure values. Regulation (EC) No 1272/2008 on classification, labelling and packaging (the CLP regulation), Part 3: Health Hazards, section 3.1.2. Criteria for classification of substances as acutely toxic part b provides for scaling of generic concentrations at 1 hour to a 4-hour LC50 as follows:

(b) Generic concentration limits for inhalation toxicity in the table are based on 4 hour testing exposures. Conversion of existing inhalation toxicity data which have been generated using a 1 hour exposure can be carried out by dividing by a factor of 2 for gases and vapours and 4 for dusts and mists.

Using the Haber's Law and a default n=1 for extrapolating to a longer exposure time as indicated in the Guidance R.7.a and CLP guidance the following converted value is obtained as a conservative estimate:

rat: inhalation LC50: >100,000 ppm, eq. to > 493,510 mg/m3
This is still far above the threshold for classification as harmful by inhalation. No classification is applicable.
Endpoint conclusion:
no study available

Data is available on the above endpoints and gave the following results:

 

Acute toxicity: Oral.

 Several sources reported the endpoint result as:

-         LD50: >1000 mg/kg (reported as the maximum feasible dose)

 

The acute oral study in this section could be waived as this route is not relevant to the expected exposure to the substance. This is in accordance with Annex VII:

 “In accordance with 8.5.1. By oral route - The study need not be conducted if a study on acute toxicity by the inhalation route (8.5.2) is available.”

 

However, it is deemed appropriate to include these data for completeness purposes. No classification is proposed for this endpoint, as the LD50 studies indicated that no toxicity is observed via the oral route at the maximum feasible dose.

 

Acute toxicity: Dermal.

This study is waived, on the basis that the route of exposure is not applicable as the substance is a gas.

 

Acute toxicity: Inhalation.

There is a number of literature references for mammalian species, and is considered appropriate for use in the scope of a weight of evidence approach. Although several sources reported exposures of 30 minutes only, and did not specify the duration of the post-treatment observation period, the data indicate that there were no effects at the highest dose tested. One additional literature reference reported similar effects following 30-min exposure and following 4 hours or 6 hours exposure in rats.

 

Review of the EU legislation does not provide for conversion from 30 min LC50 exposure values. Regulation (EC) No 1272/2008 on classification, labelling and packaging (the CLP regulation), Part 3: Health Hazards, section 3.1.2.Criteria for classification of substances as acutely toxic part b provides for scaling of generic concentrations at 1 hour to a 4-hour LC50 as follows:

 

(b) Generic concentration limits for inhalation toxicity in the table are based on 4 hour testing exposures. Conversion of existing inhalation toxicity data which have been generated using a 1 hour exposure can be carried out by dividing by a factor of 2 for gases and vapours and 4 for dusts and mists.

 

Following Guidance R.7a and Guidance onthe application of the CLP criteria, the LC50 (30min) were extrapolated to a 4 hours exposure using the Haber's Law and a default value of n=1. This is a conservative estimate. This yields the following results:

 

mouse: inhalation LC50: 95,000 ppm, i.e., 468834 mg/m3

guinea pig: inhalation LC50: >100,000 ppm i.e., > 493510 mg/m3

rabbit: inhalation LC50: >100,000 ppm i.e., > 493510 mg/m3

rat: inhalation LC50: >100,000 ppm i.e., > 493510 mg/m3

The results in rats are also supported by one study indicating no mortality following 4 or 6 hours exposure to 800 000 ppm in rats, which can be converted to 3948 g/m3. Although the post-exposure observation period was not stated. Anesthetic or narcotic effects were observed at concentrations of 70% v/v and 80% v/v.

This is still far above the threshold for classification as harmful by inhalation. No classification is applicable.


The acute toxicity was assessed by weight of evidence considering various studies and handbook data rated with reliability 2 or 4 according to the Klimish et al system. This ranking was deemed appropriate because the studies were not conducted to GLP and are not in compliance with the current standards, or with sufficient details on test conditions. However, several studies at very high concentrations, well above the recommended limit concentration, were available for the inhalation route with consistent results showing no mortality. Adverse effects reported included narcosis/anesthesia at the highest concentrations close to asphyxiating conditions. 

The above results triggered no classification under the CLP Regulation (EC No 1272/2008). No classification for acute effects is therefore required.

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Vapour pressure: 566.6 kPa at 20°C
Vapour pressure:
566.6 kPa
at the temperature of:
20 °C

Five references are available for review. The reference values closely matches the registrants experience of the substance and is considered suitable for use, on the basis of a weight of evidence approach. The value at 20 deg C is chosen as the most appropriate one for use in the assessment process, as this closely matches values obtained from the other studies.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion