Registration Dossier

Administrative data

Description of key information

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.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not specified
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Remarks:
General overview of study results is presented, in accordance with EPA reporting rule on certain pesticide inert ingredients. No specific methodology is detailed.
Guideline:
other: No test guideline mentioned
Principles of method if other than guideline:
EPA reporting rule on certain pesticide inert ingredients (Section 8 (d) of the Toxic Substances Control Act (Fed. Vol. 54, No. 38, Tuesday, February 28, 1989)). No specific methodology is detailed in the available cover letter.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
Not specified
Route of administration:
oral: unspecified
Vehicle:
not specified
Details on oral exposure:
Not specified
Doses:
Not specified
No. of animals per sex per dose:
Not specified
Control animals:
not specified
Details on study design:
Not specified
Statistics:
Not specified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 1 000 mg/kg bw
Based on:
not specified
Mortality:
No deaths
Clinical signs:
Not specified
Body weight:
Not specified
Gross pathology:
Not specified
Other findings:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 > 1000 mg/kg. It should be noted that this study could be waived as it is not relevant to the expected exposure to the substance. This is 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.”
However, this study is included as supporting information to fulfil this data endpoint.
Although a limit test at > 1000 mg/kg no classification is proposed for oral toxicity, as this route of exposure is not anticipated.
Executive summary:

LD50 > 1000 mg/kg in a limit test. This study is included as supporting information to fulfil this data endpoint.

Although a limit test at > 1000 mg/kg no classification is proposed for oral toxicity, as this route of exposure is not anticipated.

Endpoint conclusion
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.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not specified
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Test result presented presented in an overview document for EPA reporting
Qualifier:
according to guideline
Guideline:
other: Not specified
Version / remarks:
Only the results are presented in a cover letter as reporting to EPA according to Section 8 (d) of the Toxic Substances Control Act (Fed. Vol. 54, No. 38, Tuesday, February 28, 1989)
Deviations:
not specified
Principles of method if other than guideline:
EPA reporting rule on certain pesticide inert ingredients. No specific methodology is reported.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
other: species not specified.
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
Not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Details on inhalation exposure:
Not specified
Analytical verification of test atmosphere concentrations:
not specified
Remarks on duration:
Not specified
Concentrations:
Not specified
No. of animals per sex per dose:
Not specified
Control animals:
not specified
Details on study design:
Not specified
Statistics:
Not specified
Sex:
not specified
Dose descriptor:
LC50
Effect level:
> 800 000 ppm
Based on:
not specified
Sex:
not specified
Dose descriptor:
LC50
Effect level:
3 956 155.419 mg/m³ air
Based on:
not specified
Remarks on result:
other: Conversion based on ACGIH ("2010 TLVs and BEIs, Based on the Documentation of the Threshold LImit Values for Chemical Substances and Physical Agents & Biological Exposure Indices")
Mortality:
No deaths
Clinical signs:
other: Not specified
Body weight:
Not specified
Gross pathology:
Not specified
Other findings:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
LC50 > 800,000 ppm. Although limited, the data set in the report indicates that the substance is not acutely harmful by inhalation exposure, and supports the weight of evidence approach for the substance. This matches the experience of handling and use of the substance. The substance is not deemed to be classified on the basis of inhalation toxicity.
Executive summary:

LC50 > 800,000 ppm (equates to 3956155.419 mg/m3). Although limited, the data set in the report indicates that the substance is not acutely harmful by inhalation exposure, and supports the weight of evidence approach for the substance. This matches the experience of handling and use of the substance. The substance is not deemed to be classified on the basis of inhalation toxicity.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
- Principle of test: animals were exposed to concentrations of gas in air ranging from 20% to 80%
- Short description of test conditions: Animals were exposed in a chamber for 30 min, or 4h and 6 hr
- Parameters analysed / observed: mortality and 3 reflexes were observed following exposure
There was no indication on the duration of the post-exposure period.
GLP compliance:
no
Test type:
traditional method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
oxygen
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: airtight glass chamber
- Exposure chamber volume: 11L
- Method of conditioning air: the liquid gas was volatilized within the chamber by heating a beaker containing the appropriate amount of test substance
- Treatment of exhaust air: carbon dioxide produced by the animals was removed by soda lime
- Temperature, humidity, pressure in air chamber: no data

TEST ATMOSPHERE
- Brief description of analytical method used: no details
- Samples taken from breathing zone: no

VEHICLE
- Composition of vehicle: 20% oxygen
- Concentration of test material in vehicle: 80% gas / 20% oxygen
- Justification of choice of vehicle: avoid deprivation of oxygen; the oxygen consumed was automatically replenished by a small water valve connecting the chamber to the oxygen bag.

Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
ca. 30 min
Remarks on duration:
30 min, and a few animals were exposed at 80% v/v for 4 and 6h
Concentrations:
concentrations ranging from 20 to 80% v/v (by 10% increment)
No. of animals per sex per dose:
not specified
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: animals were examined immediately after the exposure period.
- Necropsy of survivors performed: no data
- Other examinations performed: clinical signs, reflexes: postural reflex, righting reflex and corneal reflex
Statistics:
no data
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
> 800 000 ppm
Based on:
test mat.
Exp. duration:
30 min
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
no death observed under the test conditions. There was no indication on the duration of the post-exposure period.
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
> 800 000 ppm
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
There was no indication on the duration of the post-exposure period.
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
> 800 000 ppm
Based on:
test mat.
Exp. duration:
6 h
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
There was no indication on the duration of the post-exposure period.
Mortality:
no mortality was observed following 30 min exposure nor in the animals exposed for 4 hours or 6 hours.
(there is no indication of the post-exposure observation period)
Clinical signs:
other: 20%: no effects observed ; 30 - 40%: muscular twitching and tremors; 70-80% no corneal reflexes, deep anesthesia
Body weight:
no data
Gross pathology:
no data
Other findings:
reflex testing showed no effect in all 3 reflexes at up to 40%.
Postural reflex was lost at concentrations at and above 50%, righting reflex was lost at 60%, corneal reflex was lost at 70%
Interpretation of results:
GHS criteria not met
Conclusions:
No mortality was observed following exposure for 30 min to concentrations up to 80% v/v. No mortality was observed following a 4hr or 6 hours exposure and reported effects were similar to the 30 min exposure. Deep narcosis was observed following 30-min exposure, or up to 6 hrs, to 70% and above.
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Taken from publically available data, and is considered accurate based on the registrants experience of the substance. It is considered appropriate for use in the scope of a weight of evidence approach.
Guideline:
other: No test guideline mentioned
Principles of method if other than guideline:
No detailed test conditions were reported in the handbook summary for the substance, except the exposure duration (30 min) and test species.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
other: mouse, guinea pig, rabbit, rat
Strain:
other: not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
Not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Details on inhalation exposure:
Not specified
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
30 min
Concentrations:
Not specified
No. of animals per sex per dose:
Not specified
Control animals:
not specified
Details on study design:
Not specified
Statistics:
Not specified
Sex:
not specified
Dose descriptor:
other: LD50
Effect level:
760 000 ppm
Based on:
not specified
Exp. duration:
30 min
Remarks on result:
other: mouse data
Sex:
not specified
Dose descriptor:
other: LD50
Effect level:
> 800 000 ppm
Based on:
not specified
Exp. duration:
30 min
Remarks on result:
other: guinea pig data
Sex:
not specified
Dose descriptor:
other: LD50
Effect level:
> 800 000 ppm
Based on:
not specified
Exp. duration:
30 min
Remarks on result:
other: rabbit data
Sex:
not specified
Dose descriptor:
other: LD50
Effect level:
> 800 000 ppm
Based on:
not specified
Exp. duration:
30 min
Remarks on result:
other: rat data
Mortality:
No mortality
Clinical signs:
other: deep narcosis
Body weight:
Not specified
Gross pathology:
Not specified
Other findings:
Not specified
Interpretation of results:
GHS criteria not met
Conclusions:
LC50 760,000 ppm, 30 min mouse
LC50 > 800,000 ppm, 30 min guinea pig, rabbit, rat
Not classified for hazardous effects.
Executive summary:

The literature data provides endpoints 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 dose tested. 

 

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.

The Guidance on the Application of the CLP criteria Version 5.0, 2017 indicates that:

Where LC50 values have been obtained in studies using exposure durations shorter or longer than 4 hours these values may be adjusted to a 4-hour equivalent using Haber’s law (C·t=k) for direct comparison with the criteria. The formula may be refined to (Cn·t=k) where the value of n, which is specific to individual substances, should be chosen using expert judgement. If an appropriate value of n is not available in the literature then it may sometimes be derived from the available mortality data using probits (i.e. the inverse cumulative distribution functions associated with the standard normal distribution). Alternatively, some default values are recommended (Guidance on IR&CSA, Section R.7.4.4.1).

For extrapolation to longer durations (in the range of approximately 30 min to 8 hrs) the Guidance on IR&CSA, section 7.4.4.1.2 indicates to set n=1.

The conversion of the approximate LC50 (30 min) to LC50 (4 hours), gives the following conservative values:

 mouse: inhalation LC50(30 min): 760,000 ppm => LC50(4hrs) ca 95,000 ppmV

guinea pig: inhalation LC50(30min): >800,000 ppm => LC50(4hrs) >100,000 ppmV

rabbit: inhalation LC50(30min): >800,000 ppm => LC50(4hrs) >100,000 ppmV

rat: inhalation LC50(30min): >800,000 ppm => LC50(4hrs) >100,000 ppmV

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

Endpoint conclusion
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.

Acute toxicity: via dermal route

Link to relevant study records
Reference
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:
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

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.


Justification for classification or non-classification

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.