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Description of key information

Skin corrosion (OECD 435): not corrosive

Overall, the available data from in vivo studies indicate a skin irritation potential.
In an eye irritation study the test item caused irritating effects in rabbits which were not reversible within 14 days.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin corrosion: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 May - 24 May 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 435 (In Vitro Membrane Barrier Test Method for Skin Corrosion)
Version / remarks:
adpoted in 2015
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: ICCVAM, Sample Protocol: “CORROSITEX® - A Validated And Accepted Dermal Corrosion Test Method For Classifying Substances According To UN Packing Groups”
Version / remarks:
adopted in 2003
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Remarks:
Landesamt für Umwelt, Mainz, Germany
Test system:
artificial membrane barrier model
Vehicle:
unchanged (no vehicle)
Details on test system:
SOURCE AND COMPOSITION OF MEMBRANE BARRIER USED
- Was the Corrositex® test kit used: Yes (InVitro International, Irvine CA, USA)
- Components: The test system consists of two components: a proteinaceous macromolecular gel (= synthetic biobarrier) on a permeable membrane and a fluid, the Chemical Detection System (CDS)
- Apparatus and preparation procedures: The biobarrier was produced on the day the assay was performed. The entire contents of the biobarrier diluent vial were added slowly to the matrix powder to ensure complete and uniform solubilisation. The vial containing the solution was placed in a water bath on a heating plate set to 68°C with the stir switch set to maintain 200 rpm for the stir bar. The solution was warmed to 68 °C and stirred for 20 min to solubilise the biobarrier matrix. Then the heating plate was switched off and the solution was left to stand for 10 minutes. In the next step 200 μL of the solubilised matrix were pipetted onto the membrane discs. The membrane discs with the biobarrier were stored in the fridge (2 - 8°C) for a period of 5 hours before use.

WAS THE COMPATIBILITY TEST PERFORMED: For the qualification screen, 108.8 mg of the test item were added to the “qualification test tube”.
The test item induced a colour change in the CDS immediately and is therefore qualified for the determination of its skin corrosion potential with the Corrositex®-Test.

WAS THE TIMESCALE CATEGORY TEST PERFORMED: The categorisation screen was used to choose the appropriate scoring scale. The screen was performed by adding 103.2 mg (tube A) and 100.4 mg (tube B) of the test item to two different test tubes (A and B) which contained an acid resp. a base buffer. The content of the individual tubes was then mixed and the resulting colours were observed after one minute.
Since no colour change could be observed in either tube, two drops of the “confirm reagent” were added to tube B; this was mixed and the resulting colour was used to confirm the category. The categorisation kit and colour chart provided by Romer Labs Deutschland GmbH were used to determine the category. The test item was classified in category 2.

TEMPERATURE USED DURING TREATMENT: no data

METHOD OF DETECTION
- Chemical detection system (CDS) was used.

METHOD OF APPLICATION: A membrane disc coated with the biobarrier was placed into a vial containing the CDS and the control resp. test item was applied. Each replicate was observed until a break-through occurred or for the maximum observation time. First, one vial was exposed to the test item and a stop watch was started. The vial was observed for 3 min. continuously. Since no colour change or any other change in the CDS was visible within 3 minutes, the remaining 3 vials were exposed to the test item in 1 minute intervals.

NUMBER OF REPLICATES: 4 vials were used for quadruplicate measurement of the test item, 4 vials were used for the positive control, 4 vials were used for the negative control and 2 vials were used as colour reference for the CDS, respectively.

NUMBER OF INDEPENDENT EXPERIMENTS TO DERIVE FINAL PREDICTION: 1

PREDICTION MODEL / DECISION CRITERIA
- The test substance is considered to be corrosive to skin if observable changes in CDS solution were observed after > 30 - 60 min (Category 1C), > 3 - 30 min (Category 1B) and 0 - 3 min (Category 1A).
- The test substance is considered to be non-corrosive to skin if observable changes in CDS solution were not observed after > 60 min.
Control samples:
yes, concurrent negative control
yes, concurrent vehicle
yes, concurrent positive control
Amount/concentration applied:
TEST MATERIAL
- Amount applied: ca. 500 mg (496.8, 505.1, 508.0 and 510.9 mg)

NEGATIVE CONTROL
- Amount applied: 500 µL
- Concentration: 10%

POSITIVE CONTROL
- Amount applied: ca. 120 mg (120.3, 122.9, 118.6 and 120.5 mg)
- Concentration: 100% (solid pellets)

Duration of treatment / exposure:
1 h (category 2)
Number of replicates:
quadruplicate measurement
Irritation / corrosion parameter:
penetration time (in minutes)
Run / experiment:
treatment with the test item
Value:
> 60
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Other effects / acceptance of results:
ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control:
The negative control did not induce a change in the colour of the CDS reagent after > 60 minutes.
- Acceptance criteria met for positive control:
The positive control showed a distinct change in the colour of the CDS reagent in the time interval of 8 - 16 minutes (recorded breakthrough times: 11 - 14 minutes).
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification as corrosive required according to Regulation (EC) No. 1272/2008
Conclusions:
Under the conditions of this test, the test substance did not show corrosive properties towards the skin in the in vitro Membrane Barrier Test for Skin Corrosion using Corrositex®.
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1964
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
12 guinea pigs were cuff-exposed to different amounts of the undiluted test item and observed for a period of two weeks
GLP compliance:
no
Species:
guinea pig
Strain:
not specified
Details on test animals or test system and environmental conditions:
no data
Type of coverage:
other: cuff
Preparation of test site:
not specified
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
0.1-20.0 mL (undiluted)
Duration of treatment / exposure:
no data
Observation period:
The animals were observed over a period of several days up to 14 days afterwards.
Number of animals:
12 guinea pigs
Irritation parameter:
erythema score
Basis:
other: no detailed information on scores available
Time point:
14 d
Reversibility:
not fully reversible within: 14 d
Remarks on result:
other: No detailed information about scores available in the publication.
Remarks:
Moderate to gross edema and erythema were observed (hemorrhagic at periphery). Scattered light to heavy scarring, grade 2 eschars or heavy black eschar breaking away at the edges and little or no hair were seen after two weeks.
Irritation parameter:
edema score
Basis:
other: no detailed information on scores available
Time point:
14 d
Reversibility:
not fully reversible within: 14 d
Remarks on result:
other: Moderate to gross edema and erythema were observed (hemorrhagic at periphery). Scattered light to heavy scarring, grade 2 eschars or heavy black eschar breaking away at the edges and little or no hair were seen after two weeks.
Irritation parameter:
erythema score
Time point:
24/48/72 h
Remarks on result:
other: No readings were recorded at these time points.
Irritation parameter:
edema score
Time point:
24/48/72 h
Remarks on result:
other: No readings were recorded at these time points.
Irritant / corrosive response data:
The following information on results is presented in the publication:

"The following symptoms were recorded on several time points (1, 2, 3, 6 days and 2 weeks) after exposure:
1, 2, 3 days: Moderate to gross edema and all of patch area and beyond necrotic to 3 erythema or hemorrhagic at perephery.
Animals hypothermic and moderate tremors.
6 days: Depressed eschar over patch, to 2 erythema at periphery, heavy desquamation at 1 week. Scattered light to heavy scarring 2 grade eschars or heavy black eschar breaking away at edges and little or no hair at 2 weeks.

A range for a LD50 value of 0.5 -1.0 mL was established.

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
CLP: Skin Corrosion 2, H315
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1964
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
One drop of the undiluted substance was instillated in the eye of one rabbit.
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
1 drop
Duration of treatment / exposure:
- single application
Observation period (in vivo):
The animals were observed at 1 h, 24 h, 48 h and up to 14 days afterwards.
Number of animals or in vitro replicates:
no data
Details on study design:
One drop of the undiluted substance was instillated in the eye of one rabbit.
Remarks on result:
other: No scores given in the publication.
Remarks:
Slight to severe erythema and edema of conjunctiva, lids and nicitating membrane as well as opaque cornea, staining and discharge were observed initially, at the 1, 24 and/or 48 hours reading. At the end of the 14-day observation period slight erythema and opaque cornea was still present.
Irritation parameter:
cornea opacity score
Time point:
24/48/72 h
Remarks on result:
other: No scores given in the publication.
Irritation parameter:
iris score
Time point:
24/48/72 h
Remarks on result:
other: No scores given in the publication.
Irritation parameter:
conjunctivae score
Time point:
24/48/72 h
Remarks on result:
other: No scores given in the publication.
Irritation parameter:
chemosis score
Time point:
24/48/72 h
Remarks on result:
other: No scores given in the publication.

The following symptoms were recorded and presented in the study report on respective time points after instillation of 1 drop in the rabbits eye:

"Initial: Erythema with slight blinking , rubbing with paw or eye held closed.

1 hour: Slight to moderate erythema of conjunctiva, lids and nicitating membrane - as well as moderate to severe edema of the same.

24 hours: Gross edema and erythema throughout, cornea opaque, purulent descharge, staining throughout.

48 hours: Erythema reduced to moderate, edema as before, purulent discharge.

14 days: Edema reduced completely, erythema only slight, cornea opaque."

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
CLP: Eye Damage 1, H318
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation / corrosion:

An in vitro membrane barrier test (Corrositex®-Test, OECD 435, Andres, 2018, key study) was performed with the test item. The test item was tested in quadruplicate and no breakthrough of the test item through the synthetic biobarrier was noted after an incubation time of 1 h. The positive, negative and vehicle controls showed the expected responses and confirmed the validity of the assay. In conclusion, it can be stated that in this test the test item did not reveal corrosive properties.

In an in vivo dermal irritation study (OTS, 1992, key study) 12 guinea pigs were dermally cuff-exposed to 0.1-20 mL of the test item. The exposure time is not specified in the report, however continuous exposure is most likely. Animals were observed for 14 days. Moderate to gross edema and erythema were observed (hemorrhagic at periphery). Scattered light to heavy scarring, grade 2 eschars or heavy black eschar breaking away at the edges and little or no hair were seen after two weeks.

In a further study (OTS, 1992, supporting study) 10 drops of 1,3-propanesultone were administered to the skin of three guinea pigs. Irritation symptoms were recorded after 24 and 48 hours as well as on day 14. The exposure time is not explicitly mentioned, but continuous exposure can be assumed. After 24 and 48 hours grade 2 to 3 erythema and slight to moderate edema were observed. At the end of the 14 -day observation period time flaky eschars were present.

After the dermal application of 0.1 mL of a 25 % solution of 1,3-propanesultone in toluene onto mouse skin ulceration has been reported as a not uncommon clinical finding shortly after application (Doak et al., 1976). The lesions healed subsequently with scarring. The substance was not removed from the skin. The animals were observed up to 78 weeks.

In the MAK evaluation (MAK, 1985) it is stated that 1,3-propanesultone has irritating effects on skin, but no further information is provided.

Conclusion:

There is clear evidence from the validated in vitro study that 1,3 –propanesultone is not corrosive to the skin. The three in vivo studies which did not follow any specific guideline and scoring system in guinea pigs and mice indicate skin effects of varying degree. Whether the effects are corrosive or irritating cannot be decucted from the documentation available. In conclusion, all available data result in classification of 1,3-propanesultone as Skin Irrit. 2 (H315).

 

Eye irritation / serious eye damage:

In a primary eye irritation study (OTS, 1992) with a 14 day observation period the following symptoms were recorded after instillation of 1 drop in the rabbits' eye: Slight to severe erythema and edema of conjunctiva, lids and nicitating membrane as well as opaque cornea, staining and discharge were observed initially, at the 1, 24 and/or 48 hours reading. At the end of the 14 -day observation period slight erythema and opaque cornea was still present.


Justification for classification or non-classification

The available data indicate that 1,3-propanesultone has no skin corrosive but skin irritating properties. Therefore, 1,3-propanesultone is subjected to classification and labelling: Skin irrit. 2 according to CLP (Regulation 1272/2008/EC).

In the eye irritation study signs of irritation were still present at the end of the 14 days observation period. Based on this result 1,3-propanesultone has to be classified with Eye damage Cat 1 according to CLP (Regulation 1272/2008/EC).