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Toxicological information

Eye irritation

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Administrative data

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)]




Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Didecyldimethylammonium chloride
EC Number:
230-525-2
EC Name:
Didecyldimethylammonium chloride
Cas Number:
7173-51-5
Molecular formula:
C22H48N.Cl
IUPAC Name:
Didecyldimethylammonium chloride
Test material form:
liquid
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

Test animals / tissue source

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

Test system

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

Results and discussion

In vivo

Resultsopen allclose all
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.

Any other information on results incl. tables

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
 

Applicant's summary and conclusion

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).

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