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Description of key information

Reliable skin irritation study with Tetrabutylphosphonium bromide performed according to GLP principles, methods used equivalent to OECD guideline 404 (Klimisch 2).

Reliable eye irritation study with Tetrabutylphosphonium bromide according to GLP principles, methods used equivalent to OECD guideline 405, but with deviations.

Based on the results of these studies, the substance does not need to be classified for skin irritation/corrosion and needs to be classified as corrosive for eye irritation/corrosion.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 June 2006 - 03 July 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study conducted according to GLP principles, methods used equivalent to OECD guideline 404.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
also application to abraded skin in the same rabbit (one animal died 4 hrs post-dose)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Millbrook Breeding Labs, Amherst, MA, USA
- Age at study initiation: 3-4 months
- Weight at study initiation: 2.5-3.4 kg
- Housing: individually in suspended cages
- Diet: PMI Rabbit Chow, provided daily
- Water: ad libitum
- Acclimation period: at least 3 days

ENVIRONMENTAL CONDITIONS
- Experiments conducted in temperature-controlled animal room
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 13 June 2006 - 03 July 2006
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5g
Duration of treatment / exposure:
4 hours
Observation period:
14 days
Number of animals:
3 (1 male and 2 females)
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm * 2.5 cm
- Type of wrap if used: surgical gauze patches were secured with non-adhesive tape, the torso was wrapped with plastic fitted with a window to allow dermal observations during the 4 hour exposure period.

REMOVAL OF TEST SUBSTANCE
- Washing (if done):no, test substance was removed by gentle wiping
- Time after start of exposure: 4 hours

SCORING SYSTEM: According to Draize, J.H., J. Pharm. Exp. Ther. 82: 377-390, 1944), additional signs were described.
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
48 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
48 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
Erythema was absent to very slight at 3 minutes after dosing and very slight to well defined at 1 and 4 hours. Edema was absent at 3 minutes after dosing, absent to very slight at 1 hour after dosing and absent to well defined at 2 hours.
At 24 hours after the 4 hour exposure, erythema was very slight to well defined. At 48 hours, erythema was well-defined and by 72 hours erythema was very slight to well defined. Edema was absent to very slight at 24, 48 and 72 hours. By day 7, erythema was absent in one animal, but very slight in another. Edema was absent on day 7. By day 14, both erythema and edema were absent.
Other effects:
One female died during 4 hour exposure period.

The results of the abraded skin are as follows:

 

 

Erythema

Eschar formation

24 hours

Mean of two animals

2

1

48 hours

Mean of two animals

2

0.5

72 hours

Mean of two animals

1.5

0.5

 

All skin effects were reversible within maximally 2 weeks.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
An in vivo skin irritancy study was conducted according to GLP principles and equivalent to OECD guidelines.Based on the outcome of this study, the test substance is not classified as corrosive or irritant to the skin.
Executive summary:

In an in vivo skin irritancy study, three rabbits were dosed with 0.5 g test substance to intact (right flank) and abraded skin (left flank). One female died within 4 hour expsoure period. Erythema was absent to very slight at 3 minutes after dosing and very slight to well defined at 1 and 4 hours. Edema was absent at 3 minutes after dosing, absent to very slight at 1 hour after dosing and absent to well defined at 2 hours. At 24 hours after the 4 hour exposure, erythema was very slight to well defined. At 48 hours, erythema was well-defined and by 72 hours erythema was very slight to well defined. Edema was absent to very slight at 24, 48 and 72 hours. By day 7, erythema was absent in one animal, but very slight in another. Edema was absent on day 7. By day 14, both erythema and edema were absent. One female died during 4 hour exposure period, however this does not influence the validity of the study as all effects in two remaining animals were reversible and scores were <2 in 2 animals. Based on the outcome of this study, it can be concluded that the test substance is not classified as corrosive or irritant to the skin.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not 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:
13 June 2006 - 03 July 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study conducted according to GLP principles, methods used equivalent to OECD guideline 404, but with deviations (0.081mg instilled instead of 0.1mg). As this amount resulted in severe effects, the test is regarded to be sufficient to fill this endpoint.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Lower amount test substance instilled, instillation into both eyes (one washed, one unwashed)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Millbrook Breeding Labs, Amherst, MA, USA
- Age at study initiation: 3-4 months
- Weight at study initiation: 3.4 kg
- Housing: individually in suspended cage
- Diet: PMI Rabbit Chow, provided daily
- Water: ad libitum
- Acclimation period: at least 3 days

ENVIRONMENTAL CONDITIONS
- Experiments conducted in temperature-controlled animal room
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 13 June 2006 - 03 July 2006
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.081mg
Duration of treatment / exposure:
Single instillation
Number of animals or in vitro replicates:
1
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): test substance was instilled in both eyes, one eye remained unwashed, one eye was flushed by lukewarm water for one minute.
- Time after start of exposure: 20 to 30 seconds

SCORING SYSTEM: Following numerical Draize technique (Draize, J.H. et al., J. Pharm. Exp. Ther. 82: 377-390, 1944), additional signs were described.

TOOL USED TO ASSESS SCORE: Mini-Maglite flashlight
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3.33
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Irritant / corrosive response data:
Corneal opacity, iritis and conjunctival irritation persisted until termination of the experiment (day 7). Pannus was noted on day 7. Discharge was noted at every observation time point.
Other effects:
Vocalization was noted post-dose.

In the washed eye, corneal opacity and iritis were noted that had cleared on day 7. Conjunctival irritation was still noticeable at day 7. Animal exhibited lethargy, prostration and laboured breathing at time of ocular dosing and instances of lethargy and few faeces post-dosing.

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
An eye irritation study was performed by instillation of 0.081mg tetrabutylphosphonium bromide in each eye of a rabbit. One eye remained unwahsed, one eye was flushed with lukewarm water. This resulted in severe effects during 7 days, after which the animal was sacrificed. Based on these results, the test substance is classified corrosive to the eye (cat. 1).
Executive summary:

An eye irritation study was performed by instillation of 0.081mg tetrabutylphosphonium bromide in each eye of a rabbit. The test was done following GLP principles. One eye remained unwashed, one eye was flushed with lukewarm water. This resulted in severe irreversible effects during 7 days in the unwashed eye, after which the animal was sacrificed. Based on these results, the test substance is classified corrosive to the eye (cat. 1).

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

In a reliable in vivo skin irritancy study (Klimisch 2), three rabbits were dosed with 0.5 g test substance to intact (right flank) and abraded skin (left flank). One female died within 4 hour exposure period. Erythema was absent to very slight at 3 minutes after dosing and very slight to well defined at 1 and 4 hours. Edema was absent at 3 minutes after dosing, absent to very slight at 1 hour after dosing and absent to well defined at 2 hours. At 24 hours after the 4 hour exposure, erythema was very slight to well defined. At 48 hours, erythema was well-defined and by 72 hours erythema was very slight to well defined. Edema was absent to very slight at 24, 48 and 72 hours. By day 7, erythema was absent in one animal, but very slight in another. Edema was absent on day 7. By day 14, both erythema and edema were absent. One female died during 4 hour exposure period, however this does not influence the validity of the study as all effects in two remaining animals were reversible and scores were <2 in 2 animals. Based on the outcome of this study, it can be concluded that the test substance is not classified as corrosive or irritant to the skin.

 

Eye irritation/corrosion:

A reliable eye irritation study (Klimisch 2) was performed by instillation of 0.081 mg tetrabutylphosphonium bromide in each eye of a rabbit. The test was done following GLP principles. One eye remained unwashed, one eye was flushed with lukewarm water. This resulted in severe irreversible effects during 7 days in the unwashed eye, after which the animal was sacrificed. Based on these results, the test substance is classified corrosive to the eye (cat. 1).

Justification for classification or non-classification

According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments), Tetrabutylphosphonium Bromide; CYPHOS® 442 Phosphonium Salt should be classified as: irreversible effects to the eye (Category 1).

According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), Tetrabutylphosphonium Bromide; CYPHOS® 442 Phosphonium Salt should be classified as Category 1 and should be labeled as H318: Causes serious eye damage.