Pentapotassium ({[(hydroxyphosphinato)methyl](phosphonatomethyl)nitroryl}methyl)phosphonate

Endpoint summary

Description of key information

The key skin irritation study, conducted in a similar manner to OECD Test Guideline 404 and in compliance with GLP, reported the test as not irritating to skin after a 4-hour semi-occlusive exposure in rabbit, with erythema and oedema scores of zero (Huntingdon Life Sciences 1996a).

The key eye irritation study, conducted according to a protocol similar to OECD Test Guideline 405 and in compliance with GLP, found the test material as mildly irritating to rabbit eyes (Huntingdon Life Sciences 1996b). The test material produced reversible conjunctival redness in two of three animals. However, the effects observed were not sufficient for classification.

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:

3 - 6 September 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Regal group UK Ltd., Great Bookham, Surrey, England
- Age at study initiation: 13 weeks
- Weight at study initiation: 3-3.1 kg
- Housing: individually in metal cages with perforated floors.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: yes, however duration unclear

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 19 °C
- Humidity (%): 30-70 %
- Air changes (per hr): ca. 19/hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
- Concentration (if solution): as supplied

Duration of treatment / exposure:

4 hours

Observation period:

Examination of the treated skin was made on Day 1 (ca. 60 minutes after removal of the dressing) and on Days 2, 3 and 4 (equivalent to 24, 48 and 72 hours after exposure).

Number of animals:

2 females and 1 male

Details on study design:

TEST SITE
- Area of exposure: dorso-lumbar
- Type of wrap if used: Each treatment site was covered with Elastoplast elastic adhesive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing: yes, with warm water. The treated area was then blotted dry with absorbent paper.
- Time after start of exposure: 4 hours

SCORING SYSTEM: Local irritation was assessed using a prescribed numerical system which ran from 0-4 for erythema and for edema, 4 being the most severe reaction.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No dermal response to treatment was observed for any animal throughout the study.

Other effects:

There were no signs of toxicity or ill health in any rabbit during the observation period.

A single semi-occlusive application of SPE9402 to intact rabbit skin for four hours elicited no dermal irritation.

Active acid 19.1%

Interpretation of results:

GHS criteria not met

Conclusions:

A skin irritation study, conducted in a similar manner to OECD 404 and in compliance with GLP, concluded that ATMP-N-oxide was not irritating to the skin of rabbit.

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:

11 - 20 September 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Regal Group UK Ltd., Great Bookham, Surrey England
- Age at study initiation: 13-15 weeks
- Weight at study initiation: 3-3.6 kg
- Housing: individually in metal cages with perforated floors.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 19°C
- Humidity (%): 30-70%
- Air changes (per hr): 19/hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml

Duration of treatment / exposure:

single instillation

Observation period (in vivo):

Examination of the eyes was made after 1 hour and 1, 2, 3 days after instillation (24, 48 and 72 hours). Additional observation was made for main study animals four days after treatment.

Number of animals or in vitro replicates:

3

Details on study design:

SCORING SYSTEM: numerical scoring system similar to Draize

TOOL USED TO ASSESS SCORE: hand-slit lamp

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.66

Max. score:

3

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

3

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.66

Max. score:

4

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Remarks on result:

probability of weak irritation

Irritant / corrosive response data:

There were no signs of toxicity or ill health in any rabbit during the observation period. No corneal damage or iridial inflammation was observed. Hyperaemia of blood vessels to a diffuse crimson colouration of the conjunctivae with slight swelling was observed, resolving in all instances four days after instillation.

Table 1: Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test

Score at time point / Reversibility	Cornea	Iris	Conjunctivae	Chemosis
60 min	0/0/0	0/0/0	2/1/1	1/1/1
24 h	0/0/0	0/0/0	2/2/1	1/2/1
48 h	0/0/0	0/0/0	1/2/1	1/1/0
72 h	0/0/0	0/0/0	1/1/1	0/0/0
Average 24h, 48h, 72h	0	0	1.3	0.7

 

 

Instillation of the test material into the rabbit eye elicited transient, very slight to well defined conjunctival irritation only.

Interpretation of results:

GHS criteria not met

Conclusions:

In an eye irritation study, conducted in a similar manner to OECD TG 405 and in compliance with GLP, ATMP-N-oxide was found mildly irritating to the eyes of rabbit.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The most reliable available studies were chosen as key, which provided sufficient information to allow for classification decision. In both key studies for skin and eye irritation, the form of substance to which animals were exposed is ATMP-N-oxide potassium salt at pH 11.3. High pH (11.3) of the test material in the key study suggests that the ATMP-N-oxide potassium salt would be severely irritating or corrosive to skin and eyes. According to the tiered approach in Regulation (EC) 1272/2008 for classification for skin irritation under EU GHS, existing human/animal data are to be considered first if available, and classification should be based on these data. A default classification derived from pH alone is only required if no reliable test data are available.

The key skin irritation study, conducted in a similar manner to OECD Test Guideline 404 and in compliance with GLP, exposed 2 female and 1 male New Zealand White rabbits to a single amount of 0.5 mL of ATMP-N-oxide-5K to the dorso-lumbar region. The treatment sites were semio-cclusive and covered with Elastoplast elastic adhesive dressing for 4 hours. After 4 hours, the treated area was washed with warm water and blotted dry with absorbent paper. The local irritation was then examined after 60 minutes and at day 2, 3 and 4 (equivalent to 24, 48 and 72 hours after exposure) after the removal of the dressing. No mortality or signs of toxicity occurred throughout the study. Additionally, no erythema or oedema at any time were observed. Therefore, it was concluded that ATMP-N-oxide-5K was not irritating to skin (Huntingdon Life Science, 1996b).

In the supporting skin irritation study, conducted in a similar manner to OECD Test Guideline 404 and in compliance with GLP, 3 male New Zealand White rabbits were exposed for 4 hours under occlusive coverage. Observations occurred at 1, 24, 48 and 72 hours after patch removal. No skin irritation at any time point, no mortality, clinical signs or behavioural alterations were observed (RBM, 1991c).

In the key eye irritation study, conducted in a similar manner to OECD Test Guideline 405 and in compliance with GLP, 1 New Zealand White rabbit was treated in advance of the other 3 rabbits to ensure that if a severe response was produced, no further animals would be exposed. The treated eye of this animal was rinsed with distilled water 30 seconds after instillation for a duration of 30 seconds. No corneal damage or iridial inflammation was observed. A diffuse crimson colouration of the conjunctivae was seen, resolving two days after treatment. 3 New Zealand White rabbits were in total treated by a single instillation of 0.1 mL of ATMP-N-oxide to the eyes. Examination of the eyes were done after 1, 24, 48 and 72 hours for cornea opacity, iris, chemosis and conjunctivae irritation. No corneal damage or iridial inflammation were observed. Hyperaemia of blood vessels to a diffuse crimson colouration of the conjunctivae with slight swelling was observed, however, this was resolving in all instances by four days after instillation. No signs of mortality or toxicity was observed in any of the animals during the observation period (Huntingdon Life Sciences, 1996b).

In a supporting eye irritation study, conducted in a similar manner to OECD Test Guideline 405 and in compliance with GLP, 3 male New Zealand White rabbits were treated with a single administration of ATMP-N-oxide. All observed endpoints evidenced that no indication of irritation occurred at any time (RBM, 1991d).

Skin and eye irritation data for ATMP-H have been included to support read-across within the ATMP and ATMP-N-Oxide Category.

In an in vivo skin irritation study with ATMP-H, conducted according to OECD Test Guideline 404 and in compliance with GLP, ATMP-H was not irritating to the skin of rabbits (SafePharm Laboratories, 1982).

In a summary of an eye irritation study with ATMP-H, conducted prior to the adoption of OECD Test Guidelines and GLP, finely ground powder of ATMP-H caused moderately severe eye irritation to rabbit eyes (Younger Laboratories, 1967c).

 

Justification for classification or non-classification

Reliable studies for skin and eye irritation of the 5K salt of ATMP-N-oxide at pH range 9.5-11.5 demonstrate no irritation. Therefore, ATMP-N-oxide 5K does not require classification for skin or eye irritation according to Regulation (EC) No 1272/2008.