Registration Dossier

Registration Dossier

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Administrative data

Description of key information

For both skin and eye irritation read across justification is presented from the structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides and from sodium nitrite to the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites.

In 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of Quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA·solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats

Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)

Group III. The di-and tri-chlorobenzyl substituted

Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g  halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded then it would seem that to consider read-across data from quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the closely structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites to be equally justifiable. In addition, for such substances the EPA deemd that "X-" could be attributed to "any ionic species" then read-across from sodium nitrite is equally justifiable.

Furthermore, in certain organic solvents it has been reported that the exchange constants between nitrite and chloride in quaternary ammonium salts (QAS) are approximately equal. (Zhurnal Analiticheskoi Khimii, 2010, Vol. 65, No. 6, pp. 579–584. (E.M. Rakhman’ko, M.S. Markovskaya, L.S. Stanishevskii, Yu.S. Zubenko, A.R. Tsyganov)

Therefore, for skin irritation two studies a presented, one from quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides and one from sodium nitrite. Similary, for eye irritation, two studies a presented, one from quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides and one from sodium nitrite.

Skin Irritation

Quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides, CAS Number 68391-05-9, EC Number 269-924-1 (1)

An OECD guideline 404 study was conducted to evaluatethe skin irritation potential of the test material(containing 80% didecyldimethylammonium chloride -DDAC, 15% isopropanol and 5% water) in rabbits.

Under the test conditions, the test material (containing 80% DDAC) was found to be corrosive to skin in rabbits and can be classified as Category 1B corrosive according to CLP Regulation (EC 1272/2008).

Quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides, CAS Number 68391-05-9, EC Number 269-924-1 (2)

A study was conducted to evaluate the skin irritation potential of the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) in New Zealand White rabbits. Study was conducted according to guideline Association of Food and Drug Officials of the US, based on Draize, 1965

A study was conducted to evaluate the skin irritation potential of the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) in New Zealand White rabbits. Study was conducted according to guideline Association of Food and Drug Officials of the US, based on Draize, 1965

The test material was applied to four test sites per rabbit (2 abraded and 2 intact) under an occlusive dressing for 24 h. Skin irritation was scored according to Draize, at patch removal, 72 and 96 h and 7 d later.

Blanching of the test sites was observed in all of the animals at 24, 72 and 96 h. Five rabbits exhibited blanching of the test sites at 7 d. Subcutaneous haemorrhage was observed within the test sites of all animals at the 72 and 96 h and 7 d observations. Eschar formation was observed within the test sites of all animals at the 7 d observation. The primary dermal irritation index (the average of the 24 and 72 hour primary dermal irritation scores) was 7.5.

Oedema scores on intact skins were 3.34, 3.92, 4 and 4 at 24, 72, 96 h and 7 d, respectively. Erythema scores on intact skins were 3.7, 4, 4, 4 at 24, 72, 96 h and 7 d, respectively. Similar results were reported on abraded skins.

Under the test conditions, the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) was considered to be corrosive to skin in rabbits and can be classified as Category 1B corrosive according to CLP Regulation (EC 1272/2008).

Sodium nitrite, CAS Number 7632-00-0, EC Number 231-555-9.

In a study reported in the screening information dataset for sodium nitrite (as a secondary source) the substance was considered not to be a skin irritant. The SIDS report references Southwood J (1985). ICI Unpublished Report No CTL/L/1003. This result is also reported in the disseminated REACH registration dossier for sodium nitrite.

Eye Irritation

Quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides, CAS Number 68391-05-9, EC Number 269-924-1

A study was performed to determine the eye irritation potential of test material(containing 75% dicocodimethylammonium chloride , 15% isopropanol and 10% water)in New Zealand White rabbits. The study was performed equivalent or similar to OECD 405.

Under the test conditions, the test material(containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) was considered to be corrosive to eyes in rabbits and can be classified as Category 1 (irreversible effects on the eye) according to CLP Regulation (EC 1272/2008).

Sodium nitrite, CAS Number 7632-00-0, EC Number 231-555-9.

In a study reported in the screening information dataset for sodium nitrite (as a secondary source) the substance was considered to be a moderate eye irritant. THe SIDS report references Southwood J (1985). ICI Unpublished Report No CTL/L/1003. This result is also reported in the disseminated REACH registration dossier for sodium nitrite.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
September 15th, 1987 to September 29th, 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Read across justification is presented from the structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites.

In 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of Quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA·solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded then it would seem that to consider read-across data from quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the closely structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites to be equally justifiable.

Furthermore, in certain organic solvents it has been reported that the exchange constants between nitrite and chloride in quaternary ammonium salts (QAS) are approximately equal. [Zhurnal Analiticheskoi Khimii, 2010, Vol. 65, No. 6, pp. 579–584. (E.M. Rakhman’ko, M.S. Markovskaya, L.S. Stanishevskii, Yu.S. Zubenko, A.R. Tsyganov)]

Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
- Name of test material (as cited in study report): Querton 210-CL-80
- Composition of test material, percentage of components: ca. 80% Didecyldimethylammonium chloride (DDAC) (CAS no.: 7173-51-5), 15% isopropanol (IPA) (CASno.: 67-63-0), remaining water
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Nottingham University, School of Agriculture, Sutton Bonington, Leicestershire, U.K.
- Age at study initiation: 12-16 wk
- Weight at study initiation: 2.19 - 2.42 kg
Type of coverage:
occlusive
Preparation of test site:
other: closely clipping the fur from the dorsal/flank areas using veterinary clippers
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
Undiluted
Duration of treatment / exposure:
Up to 60 minutes
Observation period:
The skin was assessed immediately after removal of the patch and again at 24, 48 and 72 h, and at 7 and 14 d
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: Clipped dorsal flanks
- Type of wrap if used: Occlusive patches
- 0.5 mL of test material was applied under occlusive patches on the clipped dorsal flanks of three rabbits and left for 3 min application on one flank and 60 min application on the other flank.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Gentle swabbing with cotton wool soaked in 3 % (v/v) aqueous acetic acid followed by cotton wool soaked in distilled water.

EVALUATION:
Approximately 1 h following removal of the patches and 24, 48 and 72 h and 7 and 14 d later, the test sites (a total of six) were examined for evidence of primary irritation and scored according to Draize (1959).
Irritation parameter:
erythema score
Basis:
mean
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: Eschar, moderate erythema extending beyond site, blanching of skin, scattered punctate formation
Irritation parameter:
erythema score
Basis:
mean
Time point:
48 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: Eschar, moderate erythema extending beyond site, blanching of skin, scattered punctate formation
Irritation parameter:
erythema score
Basis:
mean
Time point:
72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: Eschar, moderate erythema extending beyond site, blanching of skin, scattered punctate formation
Irritation parameter:
edema score
Basis:
mean
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: Oedema extending beyond site
Irritation parameter:
edema score
Basis:
mean
Time point:
48 h
Score:
3.6
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: Oedema extending beyond site
Irritation parameter:
edema score
Basis:
mean
Time point:
72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: Oedema extending beyond site

After three minutes exposure:

No adverse skin reaction were noted at any treated skin site 1 h after the removal of the patches. Very slight or well-defined erythema had developed at two treated skin sites at the 24 h observation and continued to be noted at  all  the  treated  sites  at the  48  and 72 h  observations. Very slight oedema was noted at one treated site at the 24 and 48 h observations and at two treated sites at the 72 h observation. 


After one hour exposure:
A light brown discoloration of the epidermis and slight haemorrhage of the dermal capillaries were noted at all treated  skin  sites 1 h  after  the  removal of the patches. Blanching of the skin was also noted at two of the skin sites. Eschar had developed at all treated skin sites at the 24 h observation and continued to be noted at the 48, 72 h and Day 7 observation. Blanching and moderate  erythema  extending  up to  approximately 7 cm beyond the treatment site were also noted at all the treated skin sites during this period. Scattered punctate eschar
surrounding two of the skin sites was also noted, with dry, straw-coloured skin evident at all the sites on Day 7. On Day 14  sunken  eschar  was  noted at all the treated skin sites. Severe oedema was noted at all the treated sites 1h after the removal of the patches. The oedema gradually decreased and appeared as very slight to slight on Day 7.  The oedema extended approximately 2 to 3 cm beyond all treated skin sites during this period. No oedema was noted on Day 14.

Interpretation of results:
Category 1B (corrosive) based on GHS criteria
Conclusions:
The test material (containing 80% didecyldimethylammonium chloride) was considered to be corrosive to skin in rabbits and can be classified as Category 1B corrosive according to CLP Regulation (EC 1272/2008).
Executive summary:

An OECD guideline 404 study was conducted to evaluatethe skin irritation potential of the test material (containing 80% didecyldimethylammonium chloride -DDAC, 15% isopropanol and 5% water) in rabbits.

The study was assigned a reliability score of 1 in accordance with the criteria for assessing data quality set forth by Klimisch et al. (1997).

Study was0.5 mL samples were applied under occlusive patches for both 3 and 60 min on the clipped skin of 3 rabbits. Residual test material was removed using cotton wool soaked in 3% (v/v) aqueous acetic acid followed by distilled water. The skin was assessed immediately after removal of the patch and again at 24, 48 and 72 h, and at 7 and 14 d.After 3 min exposure, very slight or well-defined erythema had developed at two treated skin sites at the 24 h observation and continued to be noted at all the treated sites at the 48 and 72 h observations. Very slight oedema was noted at one treated site at the 24 ad 48 h observations and at two treated sites at the 72 h observation. On Day 7 and 14, some hyperkeratinisation (2/3) and desquamation (1/3) was still present.After 1 h exposure, a light brown discolouration of the epidermis and slight haemorrhage of the dermal capillaries were noted at all treated skin sites 1 h after the removal of the patches. Blanching of the skin was also noted at two of the skin sites. Eschar had developed at all treated skin sites at the 24 h observation and continued to be noted at the 48, 72 h and Day 7 observations. Blanching and moderate erythema extending up to approximately 7 cm beyond the treatment site were also noted at all the treated skin sites during this period. Scattered punctuate eschar surrounding two of the skin sites was also noted, with dry, straw-coloured skin evident at all the sites on Day 7.On Day 14 sunken eschar was noted at all the treated skin sites. Severe oedema was noted at all the treated sites 1 h after the removal of the patches. The oedema gradually decreased and appeared as very slight to slight on Day 7. The oedema extended approximately 2 to 3 cm beyond all treated skin sites during this period. No oedema was noted on Day 14.

Under the test conditions, the test material (containing 80% DDAC) was found to be corrosive to skin in rabbits and can be classified as Category 1B corrosive according to CLP Regulation (EC 1272/2008).

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
From May 28, 1980 to June 4, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Read across justification is presented from the structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites.

In 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of Quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA·solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded then it would seem that to consider read-across data from quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the closely structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites to be equally justifiable.

Furthermore, in certain organic solvents it has been reported that the exchange constants between nitrite and chloride in quaternary ammonium salts (QAS) are approximately equal. [Zhurnal Analiticheskoi Khimii, 2010, Vol. 65, No. 6, pp. 579–584. (E.M. Rakhman’ko, M.S. Markovskaya, L.S. Stanishevskii, Yu.S. Zubenko, A.R. Tsyganov)]

Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
other: Association of Food and Drug Officials of the US, based on Draize, 1965
Deviations:
not specified
GLP compliance:
no
Remarks:
Pre GLP
Specific details on test material used for the study:
- Name of test material (as cited in study report): Arquad 2C
- Composition of test material, percentage of components: 75% dicocodimethylammonium chloride (CAS no. 61789-77-3), 15% isopropanol and 10% water
- Lot/batch No.: #1001702
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dutchland Laboratories, Inc., Denver, Penn. USA
- Age at study initiation: ca. 14 wk
- Weight at study initiation: 2509 - 2813 g
- Housing: Individually in screen bottom cages
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: 14 d

IN-LIFE DATES: From: 28 May 1980 To: 4 June 1980
Type of coverage:
occlusive
Preparation of test site:
other: clipped and abraded
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): Neat material
Duration of treatment / exposure:
24 h
Observation period:
After treatment, at 72 h (48 h after patch removal), and if signs of irritation had increased at 96 h (72 h after patch removal) and 7 d (6 d after patch removal).
Number of animals:
3 males and 3 females
Details on study design:
TEST SITE
- Area of exposure: Not indicated
- Area of coverage: 5.0 x 5.0 cm gauze patch
- Type of wrap if used: Saran wrap and elstoplast tape, plus collars


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Test material was wiped (not washed)
- Time after start of exposure: After 24 h

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Test material was wiped (not washed)
- Time after start of exposure: After 24 h

SCORING SYSTEM:
EVALUATION OF SKIN REACTIONS
A. Erythema and eschar formation
No erythema 0
Doubtful or barely perceptible 0.5
Very slight erythema 1
Slight not well defined 1.5
Well-defined erythema 2
Moderate 2.5
Moderate to severe erythema 3
Severe not beet red 3.5
Severe erythema (beet redness) to slight eschar
formation (injuries in depth) 4

B. Oedema formation
No oedema 0
Doubtful or barely perceptible 0.5
Very slight oedema 1
Slight not well defined 1.5
Slight oedema (edges of area well-defined by
definite raising) 2
Edges well defined but less than 1 mm 2.5
Moderate oedema (raised approximately 1 mm) 3
Greater than 1 mm, exposure area only or 1 mm
extending beyond exposure area 3.5
Severe oedema (raised more than 1 mm and
extending beyond area of exposure) 4
Irritation parameter:
edema score
Basis:
mean
Time point:
24 h
Score:
3.34
Max. score:
3.5
Reversibility:
not reversible
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
mean
Time point:
72 h
Score:
3.92
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 96 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
mean
Time point:
7 d
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
24 h
Score:
3.7
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
72 h
Score:
4
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 96 h
Score:
4
Max. score:
4
Reversibility:
other:
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
7 d
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
mean
Time point:
24 h
Score:
3.46
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: abraded skin
Irritation parameter:
edema score
Basis:
mean
Time point:
72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: abraded skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 96 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: abraded skin
Irritation parameter:
edema score
Basis:
mean
Time point:
7 d
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: abraded skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
24 h
Score:
3.67
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: abraded skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
72 h
Score:
3.88
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: abraded skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 96 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: abraded skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
7 d
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: abraded skin
Irritant / corrosive response data:
- Blanching of the test sites was observed in all the animals at 24, 72 and 96 h readings (0, 48 and 72 h after patch removal).
- Five animals exhibited blanching of the test sites at 7 d.
- Subcutaneous hemorrhage was observed within the test sites of all animals at the 72 and 96 h and 7 d readings.
- Eschar formation was observed within the test sites of all animals at the 7 d observation
Other effects:
None

Table 1. Summary of dermal lesions (following 24-h application); mean of two intact sites

Animal no.

Effect

Hour

Days after patch removal 

Mean score erythema

(48/72 h)

Mean score oedema

(48/72 h)

0

1

2

3

6

14

3153

M

Erythema

Oedema

3.5 AB

4.0

-

-

3.5 BC

4.0

4.0 BC

4.0

4.0 CE

4.0

-

-

3.75

4.0

3152

M

Erythema

Oedema

3.2 AB

3.5

-

-

4.0 BC

4.0

4.0 BC

4.0

4.0 CE

4.0

-

-

4.0

4.0

3151

M

Erythema

Oedema

3.0 AB

4.0

-

-

4.0 BC

4.0

4.0 BC

4.0

4.0 BCE

4.0

-

-

4.0

4.0

3206

F

Erythema

Oedema

3.5 AB

3.8

-

-

4.0 BC

3.8

4.0 BC

4.0

4.0 BCE

4.0

-

-

4.0

3.9

3196

F

Erythema

Oedema

3.5 AB

3.5

-

-

4.0 BC

4.0

4.0 BC

4.0

4.0 CE

4.0

-

-

4.0

4.0

3197

F

Erythema

Oedema

3.2 AB

3.5

-

-

4.0 BC

4.0

4.0 BC

4.0

4.0 BCE

4.0

-

-

4.0

4.0

Mean all animals

3.96

3.98

A = erythema scored on edge of blanching; B = blanching at entire test site; C = subcutaneous haemorrhage and all test sites appeared to have slight to moderate eschar formation; E = eschar

Interpretation of results:
Category 1 (corrosive) based on GHS criteria
Conclusions:
Under the test conditions, the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) was considered to be corrosive to skin in rabbits and can be classified as Category 1B corrosive according to CLP Regulation (EC 1272/2008).
Executive summary:
A study was conducted to evaluate the skin irritation potential of the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) in New Zealand White rabbits. Study was conducted according to guideline Association of Food and Drug Officials of the US, based on Draize, 1965

The study was assigned a reliability score of 2 in accordance with the criteria for assessing data quality set forth by Klimisch et al. (1997).

A study was conducted to evaluate the skin irritation potential of the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) in New Zealand White rabbits. Study was conducted according to guideline Association of Food and Drug Officials of the US, based on Draize, 1965

The test material was applied to four test sites per rabbit (2 abraded and 2 intact) under an occlusive dressing for 24 h. Skin irritation was scored according to Draize, at patch removal, 72 and 96 h and 7 d later.

Blanching of the test sites was observed in all of the animals at 24, 72 and 96 h. Five rabbits exhibited blanching of the test sites at 7 d. Subcutaneous haemorrhage was observed within the test sites of all animals at the 72 and 96 h and 7 d observations. Eschar formation was observed within the test sites of all animals at the 7 d observation. The primary dermal irritation index (the average of the 24 and 72 hour primary dermal irritation scores) was 7.5.

Oedema scores on intact skins were 3.34, 3.92, 4 and 4 at 24, 72, 96 h and 7 d, respectively. Erythema scores on intact skins were 3.7, 4, 4, 4 at 24, 72, 96 h and 7 d, respectively. Similar results were reported on abraded skins.

Under the test conditions, the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) was considered to be corrosive to skin in rabbits and can be classified as Category 1B corrosive according to CLP Regulation (EC 1272/2008).

Endpoint:
skin irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1985
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Justification for type of information:
It is suggested that read-across data from sodium nitrite is considered appropriate in order to arrive at a conclusion in terms of any health effects that may be incurred from exposure to "nitrite" whichever cation it may be associated with.

In 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded and that the counter anion could be regarded as "any anionic species" then it would seem that to consider available toxicological data on sodium nitrite, in order to evaluate any health effects that may be incurred from exposure to the nitrite anion (NO2-), is justifiable.

Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not specified
Principles of method if other than guideline:
In a reliable study for skin irritation in rabbits, performed using a method similar to OECD TG 404 but not under GLP, approximately 500 mg of the substance was applied to the shaved backs of 6 male New Zealand White rabbits and covered with a semi-occlusive dressing for four hours. The animals were examined one hour, one, two and three days after removal of the chemical. Some slight irritation was observed one hour after removal of the substance, but all signs had disappeared by the one day observation and the substance is not considered to be a skin irritant.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
ca 500 mg
Duration of treatment / exposure:
4 hours
Observation period:
The animals were examined one hour, one, two and three days after removal of the chemical.
Number of animals:
6 male New Zealand White rabbits
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
24 h
Score:
0
Reversibility:
fully reversible
Remarks on result:
other: Some slight irritation was observed one hour after removal of the substance, but all signs had disappeared by the one day observation and the substance is not considered to be a skin irritant.
Irritant / corrosive response data:
Some slight irritation was observed one hour after removal of the substance, but all signs had disappeared by the one day observation and the substance is not considered to be a skin irritant.
Interpretation of results:
GHS criteria not met
Conclusions:
In a study reported in the screening information dataset for sodium nitrite (as a secondary source) the substance was considered not to be a skin irritant. THe SIDS report references Southwood J (1985). ICI Unpublished Report No CTL/L/1003. This result is also reported in the disseminated REACH registration dossier for sodium nitrite.
Executive summary:

The skin irritation potential of the test substance has been investigated in a study reported in the screening information dataset (SIDS) for sodium nitrite as a secondary source which in turn reports Southwood J (1985). ICI Unpublished Report No CTL/L/1003 as the primary source. The study is reported as reliable in the SIDS dossier and was performed using a method similar to OECD TG 404. The study was not conducted to GLP.

Similarly this study is also referenced in the disseminated REACH registration dossier for sodium nitrite. However, in this dossier, the study is assigned a reliability score of 4 in accordance with the criteria for assessing data quality set forth by Klimisch et.al (1997).

Under the conditions of the study approximately 500 mg of the substance was applied to the shaved backs of 6 male New Zealand White rabbits and covered with a semi-occlusive dressing for four hours. The

animals were examined one hour, one, two and three days after removal of the chemical. Some slight irritation was observed one hour after removal of the substance, but all signs had disappeared by the one day observation and the substance is not considered to be a skin irritant.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
May 27th, 1980 to June 17th, 1980.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Read across justification is presented from the structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites.

In 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of Quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA·solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded then it would seem that to consider read-across data from quaternary ammonium compounds, di-C12-18-alkyldimethyl, chlorides to the closely structurally analogous quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites to be equally justifiable.

Furthermore, in certain organic solvents it has been reported that the exchange constants between nitrite and chloride in quaternary ammonium salts (QAS) are approximately equal. [Zhurnal Analiticheskoi Khimii, 2010, Vol. 65, No. 6, pp. 579–584. (E.M. Rakhman’ko, M.S. Markovskaya, L.S. Stanishevskii, Yu.S. Zubenko, A.R. Tsyganov)]




Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Remarks:
Pre-GLP
Specific details on test material used for the study:
- Name of test material (as cited in study report): Arquad 2C
- Composition of test material, percentage of components: 75% dicocodimethylammonium chloride (CAS no. 68391-05-9), 15% isopropanol and 10% water
- Physical state: Liquid
- Lot No.: 1001702
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hoppers Unlimited, Verona, WI, USA
- Age at study initiation: ca. 14 wk
- Housing: Individually in screen bottom cages
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: at least 7 d


IN-LIFE DATES: From: 28 May To: 17 June 1980
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated left eye of each animal served as the control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): neat material
Duration of treatment / exposure:
Two groups of animals were used, in one group (II) the eyes were washed after 30 sec exposure and in the other group the eyes were not washed (I). The study continued to 21 d
Observation period (in vivo):
Readings were done after 24, 48, 72 and 96 h and after 7, 14 and 21 d. At the 72 h, 7, 14 and 21 d reading sodium fluorescein and UV light were used.
Number of animals or in vitro replicates:
Group I: 6 animals
Group II: 3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): in 3 out of 9 rabbits, the eyes of the other 6 remained unflushed.
- Time after start of exposure: ca. 30 sec.

1. CORNEA
(A) Degree of Opacity (most dense area used)
No opacity 0
Scattered or diffuse areas, details of iris clearly visible 1
Easily discernible translucent areas, details of iris slightly obscured 2
Opalescent areas, no details of iris visible, size of pupil barely discernible 3
Opaque, iris invisible 4
(B) Area of Cornea involved
One quarter (or less) but not zero 1
Greater than one quarter but less than half 2
Greater than half but less than three quarters 3
Greater than three quarters, up to whole area 4
THE TOTAL SCORE = (A x B) x 5, MAXIMUM TOTAL = 80

2. IRIS
(A) Values
Normal 0
Folds above normal, congestion, swelling, circumcorneal injection (any or all of these or combination of any thereof), iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, haemorrhage, gross destruction (any or all of these) 2
THE TOTAL SCORE = A x 5, MAXIMUM TOTAL = 10

3. CONJUNCTIVAE
(A) Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Vessels normal 0
Vessels definitely injected above normal 1
More diffuse, deeper crimson red, indiviual vessels not easily discernible 2
Diffuse beefy red 3
(B) Chemosis
No swelling 0
Any swelling above normal (includes nictitating membrane) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids half closed to completely closed 4
(C) Discharge
No discharge 0
Any amount different from normal (does not include small amounts observed in inner canthus of normal animals) 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs and considerable area around the eye 3
THE TOTAL SCORE (A + B + C) x 2, MAXIMUM TOTAL = 20

MAXIMUM TOTAL SCORE POSSIBLE = 110
NB In this scoring system also half grades were used (0.5, 1.5, 2.5, or 3.5)

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
3.89
Max. score:
4
Reversibility:
not reversible
Remarks:
within 21 d
Remarks on result:
other: Unwashed eyes
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
not reversible
Remarks:
within 21 d
Remarks on result:
other: Unwashed eyes
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
not reversible
Remarks:
within 21 d
Remarks on result:
other: Unwashed eyes
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
within 21 d
Remarks on result:
other: Unwashed eyes
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Remarks:
within 21 d
Remarks on result:
other: Washed eyes
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
1.33
Max. score:
2
Reversibility:
not reversible
Remarks:
within 21 d
Remarks on result:
other: Washed eyes
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Remarks:
within 21 d
Remarks on result:
other: Washed eyes
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks:
within 21 d
Remarks on result:
other: Washed eyes
Irritant / corrosive response data:
- Blanching and areas of necrosis were observed in the conjunctivae of all rabbits at the 24, 48, 72, 96 h and 7 and 14 d readings and in 3 rabbits at 21 d.
- Hypopyon was observed in 4 rabbits at 7 d.
- Red ocular discharge was exhibited in 3 animals at 7 d and in 2 animals at 14 d.
- Panophthalmitis was exhibited by 1 animal at 14 days and by all animals at 21 days.

Table 1. Eye irritation scores (Draize) in rabbits exposed to 0.1 mL test substance and the eyes was not washed

Time

Corneal Opacity

Iris

 

2997

2999

2947

3057

3051

3050

2997

2999

2947

3057

3051

3050

24 h

4

3

4

3

4

4

2m

2m

2m

2m

2m

2m

48h

4

4

4

4

4

4

2m

2m

2m

2m

2m

2m

72h

4

4

4

4

4

4

2m

2m

2m

2m

2m

2m

96 h

4

4

4

4

4

4

2m

2m

2m

2m

2m

2m

7 d

3.5k

3.5k

m

3.5k

m

3.5k

2m

2m

2m

2m

2m

2m

14 d

4

4

4

q

4

4

2m

2m

2m

2m

2m

2m

21 d

q

q

q

q

q

q

q

q

q

q

q

q

Mean 24-72 h

4

3.67

4

3.67

4

4

2

2

2

2

2

2

 

Time

Conjunctivae - Redness

Conjunctivae - Chemosis

Conjunctivae - Discharge

 

2997

2999

2947

3057

3051

3050

2997

2999

2947

3057

3051

3050

2997

2999

2947

3057

3051

3050

24 h

1

1

1

1

1

1

4

4

4

4

4

4

3a

3a

3a

3a

3a

3a

48 h

0jd

0jd

0jd

0jd

0jd

0jd

4

4

4

4

4

4

3a

3a

3a

3a

3a

3a

72 h

0jd

0jd

0jd

0jd

0jd

0jd

4

4

4

4

4

4

3a

3a

3a

3a

3a

3a

96 h

0jd

0jd

0jd

0jd

0jd

0jd

4

4

4

4

4

4

3a

3a

3a

3a

3a

3a

7 d

0

0

m

0

m

0

4

3.5

4

4

4

3.5

2a

2.5a

3pa

3pa

3a

2.5pa

14 d

2jd

2jd

2jdl

ljdm

2jdl

2jdl

4

4

4

4

4

4

3ap

2a

2a

2a

2a

2ap

21 d

2jd

2jd

m

m

m

2.5

3

3.5

4

3

3.5

4

2.5a

2a

1a

1a

2a

2a

Mean 24-72 h

0.33

0.33

0.33

0.33

0.33

0.33

4

4

4

4

4

4

3

3

3

3

3

3

a Purulent discharge

d Blanching

k hypopyon

l Hair loss around the eye

J Conjunctivae appear necrotic

m Unable to visualise

p red discharge

q Panopthalmitis

Table 2. Eye irritation scores (Draize) in rabbits exposed to 0.1 mL test substance and the eyes was flushed for one minute

Time

Corneal Opacity

Iris

Conjunctivae - redness

Conjunctivae- chemosis

Conjunctivae- discharge

2958

2935

3018

2958

2935

3018

2958

2935

3018

2958

2935

3018

2958

2935

3018

24 h

1.5

3

1.5

1inj

2m

1inj

2jd

2jd

2jd

4

4

4

3a

3a

3a

48h

1

3

1.5

1inj

2m

1inj

2jd

0jd

1jd

4

4

4

3a

3a

3a

72h

2

3

1.5

1inj

2m

1inj

3jd

3jd

3jd

4

4

4

3pa

3a

3a

96 h

1.5

4

1.5

1inj

2m

1inj

3jd

3jd

3jd

4

4

4

3pa

3a

3pa

7 d

3.5k

4k

3

1inj

2m

1inj

3cjd

0jd

3cjd

4

4

3.5

3a

3a

3a

14 d

4h

4

4h

2m

2m

2m

2jd

2jdl

2cjd

2

4

4

1.5a

2a

2a

21 d

4

q

4

2m

q

2m

2.5cjd

2.5jd

3.0kcjd

3

4

3

3a

2.5p

3a

Mean 24-72 h

1.5

3

1.5

1

2

1

2.3

1.67

2

4

4

4

3

3

3



a Purulent discharge

c Petite hemorrhage

d Blanching

k Conjunctivae appears necrotic

j Conjunctivae appears necrotic

inj Injected

m Unable to visualise

p Red discharge

q Panopthalmitis
 
Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
Under the test conditions, the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) was considered to be corrosive to eyes in rabbits and can be classified as Category 1 (irreversible effects on the eye) according to CLP Regulation (EC 1272/2008).
Executive summary:

A study was performed to determine the eye irritation potential of test material (containing 75% dicocodimethylammonium chloride , 15% isopropanol and 10% water) in New Zealand White rabbits. The study was performed equivalent or similar to OECD 405.

The study was assigned a reliability score of 2 in accordance with the criteria for assessing data quality set forth by Klimisch et al. (1997).

Two groups of New Zealand white rabbits were used to in the study.0.1 ml test material was instilled into the eye of 9 rabbits (leaving the other eye untreated as a control).In one group (with 3 animals) the eyes were washed after 30 sec exposure and in the other group (with 6 animals) the eyes were not flushed. Readings (according to Draize) were done after 24, 48, 72 and 96 h and after 7, 14 and 21 d. At the 72 h, 7, 14 and 21 d reading sodium fluorescein and UV light were used. Blanching and areas of necrosis were observed in the conjunctivae of all rabbits at the 24, 48, 72 and 96 h and 7 and 14 d readings and in three animals at 21 d. Hypopyon was observed in four animals at 7 d. Red ocular discharge was exhibited in three animals at the 7 d and two animals at 14 d. Panopthalmitis was exhibited by one animal at 14 d and by all animals at 21 d.

Under the test conditions, the test material (containing 75% dicocodimethylammonium chloride, 15% isopropanol and 10% water) was considered to be corrosive to eyes in rabbits and can be classified as Category 1 (irreversible effects on the eye) according to CLP Regulation (EC 1272/2008).

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1985
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
It is suggested that read-across data from sodium nitrite is considered appropriate in order to arrive at a conclusion in terms of any health effects that may be incurred from exposure to "nitrite" whichever cation it may be associated with.

In 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded and that the counter anion could be regarded as "any anionic species" then it would seem that to consider available toxicological data on sodium nitrite, in order to evaluate any health effects that may be incurred from exposure to the nitrite anion (NO2-), is justifiable.

Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
other: Untreated eye of the test animal
Amount / concentration applied:
100 mg
Duration of treatment / exposure:
30 - 60 seconds
Observation period (in vivo):
12 days
Number of animals or in vitro replicates:
6
Details on study design:
In a reliable study for eye irritation in rabbits, performed using a method similar to OECD TG 405 but not under GLP, 100 mg of substance was applied into the conjunctival sac of the left eye of six female New Zealand White Rabbits. The eyes of three of the rabbits were irrigated with water for two minutes 30 – 60 seconds after application of the substance. Conjunctival effects were seen in all animals and consisted of moderate redness, mild chemosis and severe discharge. All signs of irritation had disappeared by twelve days. No corneal effects were observed.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Remarks on result:
not measured/tested
Irritation parameter:
conjunctivae score
Basis:
mean
Reversibility:
fully reversible within: 12 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
mean
Reversibility:
fully reversible within: 12 days
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
Conjunctival effects were seen in all animals and consisted of moderate redness, mild chemosis and severe discharge. All signs of irritation had disappeared by twelve days. No corneal effects were observed.
Interpretation of results:
Category 2B (mildly irritating to eyes) based on GHS criteria
Conclusions:
In a study reported in the screening information dataset for sodium nitrite (as a secondary source) the substance was considered to be a moderate eye irritant. THe SIDS report references Southwood J (1985). ICI Unpublished Report No CTL/L/1003. This result is also reported in the disseminated REACH registration dossier for sodium nitrite.
Executive summary:

The eye irritation potential of the test substance has been investigated in a study reported in the screening information dataset (SIDS) for sodium nitrite as a secondary source which in turn reports Southwood J (1985). ICI Unpublished Report No CTL/L/1003 as the primary source. The study is reported as reliable in the SIDS dossier and was performed using a method similar to OECD TG 405. The study was not conducted to GLP.

Similarly this study is also referenced in the disseminated REACH registration dossier for sodium nitrite. However, in this dossier, the study is assigned a reliability score of 4 in accordance with the criteria for assessing data quality set forth by Klimisch et.al (1997).

Under the conditions of the study 100 mg of substance was applied into the conjunctival sac of the left eye of six female New Zealand White Rabbits. The eyes of three of the rabbits were irrigated with water for two minutes 30 – 60 seconds after application of the substance. Conjunctival effects were seen in all animals and consisted of moderate redness, mild chemosis and severe discharge. All signs of irritation had disappeared by twelve days. No corneal effects were observed.

The substance is regarded to be a moderate eye irritant.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

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