Tetrakis(hydroxymethyl)phosphonium chloride

Endpoint summary

Description of key information

- By analogy, the test substance is considered as a skin sensitizer (OECD 406, Kr.2, GLP).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

No data on skin sensitisation are available for THPC. However, a similar substance (THPS) was demonstrated to be skin sensitiser (Guess, 1994). Information from THPS is judged relevant because as an ionic salt, THPC is completely dissociated into THP+ and Cl- in aqueous solutions and the equivalent is true for most of the THP+ salts, including sulphate salt. As a consequence hazard properties evaluated in aqueous solution could reasonably be predicted using data from the equivalent sulphate salt. Therefore a read-across approach could be done for certain hazard properties between THPC (chloride salt) and THPS (sulphate salt).

Reason / purpose for cross-reference:

read-across source

Key result

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

75% (v/v)

No. with + reactions:

14

Total no. in group:

20

Clinical observations:

oedema, erythema, grey/green coloured dermal necrosis beyond the challenge site and a dark brown- coloured scab adjacent to to the challenge site.

Remarks on result:

positive indication of skin sensitisation

Key result

Reading:

1st reading

Hours after challenge:

48

Group:

negative control

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

no indication of skin sensitisation

Key result

Reading:

1st reading

Hours after challenge:

48

Group:

positive control

Remarks on result:

not measured/tested

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

November- december 1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study, performed according to standard method, read-across with THPC.

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

yes

Remarks:

see below

Qualifier:

according to guideline

Guideline:

EPA OPP 81-6 (Skin Sensitisation)

Deviations:

yes

Remarks:

see below

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

Deviations:

yes

Remarks:

see below

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4100 (Skin Sensitisation)

Deviations:

yes

Remarks:

see below

Principles of method if other than guideline:

Deviations from the current OECD 406 (17/07/1992) test guideline:
The grading scale was from 0 to 4 both for erythema and oedema formation, according to Draize (1959), instead of 0 to 3 for erythema
formation as described in the OECD guideline 406.

GLP compliance:

yes (incl. QA statement)

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

Study performed before the adoption of the OECD 429 guideline.

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: David Hall Ltd., UK
- Age at study initiation: 8-12 weeks old
- Weight at study initiation: 333-410 g
- Housing: in groups of up to three in solid-floor polypropylene cages furnished with woodflakes
- Diet/ water : Free access to mains tap water and food
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-22°C
- Humidity: 50-66%
- Air changes (per hr): 15
- Photoperiod: 12 hr dark / 12 hr light

IN-LIFE DATES: From 16 November 1993 to 24 December 1993

Route:

intradermal and epicutaneous

Vehicle:

water

Concentration / amount:

see below, details on study design

Route:

epicutaneous, occlusive

Vehicle:

water

Concentration / amount:

see below, details on study design

No. of animals per dose:

30 (20 in the test group; 10 in the control group)

Details on study design:

RANGE FINDING TESTS:
The selection of the concentrations used for the induction and challenge phases (see above) in the main study was based on the results of the pilot studies.
For the selection of concentration for topical challenge, the tested concentration range, 4 concentrations from 5 to 50 % v/v (as active substance; THPS 75%) for 24 hours, none of the two tested guinea pigs showed any skin reaction. According to this result, it was decided to use the highest tested concentration inducing no irritation effect (50 % v/v active substance) on one flank region and a higher concentration ensuring a positive skin reaction (75 % v/v) on the other flank side.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2
1st application: Induction 0.1 % intracutaneous (day 0)
2nd application: Induction 25 % occlusive epicutaneous (day 7)
- Site: the shoulder region of each animal
- Duration: 48h
Concentrations for induction: (day 0 and 7)
Intradermal induction: 0.1% w/v in distilled water, that is 0.75 µg main ingredient/mL,
Topical induction: 25% v/v in distilled water, that is 34.8 µg active substance/mL or 26.1 µg main ingredient/mL.

B. CHALLENGE EXPOSURE
- No. of exposures: 1
3rd application: Challenge 75 % occlusive epicutaneous
- Day(s) of challenge: 21
- Exposure period: test substance was removed using water 24 hours following application
- Site: the shorn right flank of each animal
Two concentrations were used for challenge: (day 21)
- 50% v/v in distilled water (69.6 µg active substance/mL or 52.2 µg main ingredient/mL) applied on the left flank, which is the highest concentration producing no evidence of skin irritation 24 and 48 hours after dressing removal,
- and 75% v/v in distilled water (104.4 µg active substance/mL or 78.3 µg main ingredient/mL) applied on the right flank, to ensure that the maximum non-irritant concentration (50 % v/v) was really used at challenge.
- examination: skin response, bodyweight
- Evaluation: 24 and 48 h after challenge

Challenge controls:

10 animals

Positive control substance(s):

no

Positive control results:

not applicable

Key result

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

75% (v/v)

No. with + reactions:

14

Total no. in group:

20

Clinical observations:

oedema, erythema, grey/green coloured dermal necrosis beyond the challenge site and a dark brown- coloured scab adjacent to to the challenge site.

Remarks on result:

positive indication of skin sensitisation

Key result

Reading:

1st reading

Hours after challenge:

48

Group:

negative control

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

no indication of skin sensitisation

Key result

Reading:

1st reading

Hours after challenge:

48

Group:

positive control

Remarks on result:

not measured/tested

After an injection of 0.1 % w/v of the test material, a topical induction  at 25 % seven days after the injection, and a topical challenge at 50 % on day 

21 post-injection, fourteen guinea pigs on the twenty treated  animals showed irritation signs, against non from the control group. The  test material 

produced a 70% sensitization rate and was classified as a strong sensitiser to guinea pig skin.

Considering a relative density of 1.392 and a THPS  concentration of 75 %, exposure concentrations expressed as main ingredient are 

as follow:
(1) intradermal induction: 0.075 % w/v = 0.75 g/L
(2) topical induction: 26.1 g/L
(3) topical challenge: 52.2 g/L

Main skin reactions for each step were:
(1) Intradermal induction:
Very slight to well defined erythemafor all test group animals at hour 24 post-injection and in eighteen test group animals ot the 48-hour observation. 

Very slight erythema was noted at the vehicle intradermal  injection sites of five control group animals at the 24-hour observation;  all control animals

recovered at hour 48 post-injection.

(2) Topical induction:
Very slight to well-defined erythema with or without very slight oedema was noted at the induction sites of eleven test group animals one hour after 

dressing removal. Only erythema was noted for 4 animals at the 24-hour observation. No skin reactions were noted at the treatment sites of control 

group animals at the one and 24-hour observations.

(3) Topical challenge:
Positive sensitisation responses, identified as very slight to  well-defined erythema with or without very slight to slight oedema, were  noted at the 

challenge sites of fourteen test four animals at the 24 and  48-hour observations. The skin reactions extended beyond challenge sites of five test 

animals on hour 24 post-application and four test animals on  hour 48. Skin exposure to a test material concentration of 75 % showed skin reactions 

from very slight to moderate erythema and oedema for all  test animals.
No skin reaction was observed at the challenge sites of control group animals at the 24 and 48-hour observations. Only a focal necrosis was  

noted for one control animal on hours 24 and 48 post-application.

Interpretation of results:

Category 1 (skin sensitising) based on GHS criteria

Conclusions:

By analogy, the test substance is classified as a skin sensitizer according to EU criteria.

Executive summary:

This skin sensitisation test was performed with THPS 75% in water with male albino guinea pigs, according to the OECD Guideline 406. Twenty test and ten control animals were used for the main study. Based on the results of the pilot tests, the concentrations of test material were 0.1 % (w/v) and 25 % (v/v) for the intradermal and topical applications of the induction phase, respectively, and 50 % or 75 % (v/v) in the challenge phase.

Expressed as main ingredient, the used concentrations were as follows, considering a THPS concentration of 75 %:

- Intradermal induction:       0.1 %w/v of THPS 75 % = 0.75 µg/mL,

- Topical induction:             25 % v/v of THPS 75 % = 26.1 µg/mL,

- Topical challenge:              50 % v/v of THPS 75 % = 52.2 µg/mL

75 % v/v of THPS 75 % = 78.3 µg/mL

Main skin reactions for each step were:

(1) Intradermal induction:

Very slight to well defined erythema for all test group animals at hour 24 post-injection and in eighteen test group animals at the 48-hour observation. Very slight erythema was noted at the vehicle intradermal injection sites of five control group animals at the 24-hour observation; all control animals recovered at hour 48 post-injection.

(2) Topical induction:

Very slight to well-defined erythema with or without very slight oedema was noted at the induction sites of eleven test group animals one hour after dressing removal. Only erythema was noted for 4 animals at the 24-hour observation. No skin reactions were noted at the treatment sites of control group animals at the one and 24-hour observations.

(3) Topical challenge:

 Positive sensitisation responses, identified as very slight to well-defined erythema with or without very slight to slight oedema, were noted at the challenge sites of fourteen test animals at the 24 and 48-hour observations. The skin reactions extended beyond challenge sites of five test animals on hour 24 post-application and four test animals on hour 48. Skin exposure to a test material concentration of 75 % showed skin reactions from very slight to moderate erythema and oedema for all test animals.

No skin reaction was observed at the challenge sites of control group animals at the 24 and 48-hour observations.

In conclusion, THPS appears to be a strong sensitizer as it produced a 70% (14/20) sensitisation rate on guinea pig skin.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

No data on skin sensitisation are available for THPC. However, a similar substance (THPS) was demonstrated to be skin sensitiser (Guess, 1994). Information from THPS is judged relevant because as an ionic salt, THPC is completely dissociated into THP+ and Cl- in aqueous solutions and the equivalent is true for most of the THP+ salts, including sulphate salt. As a consequence hazard properties evaluated in aqueous solution could reasonably be predicted using data from the equivalent sulphate salt. Therefore a read-across approach could be done for certain hazard properties between THPC (chloride salt) and THPS (sulphate salt).
THPC is characterised by corrosive properties; then according to Column 2 of the REACH regulation (1907/2006) studies on skin sensitisation should not be conducted. However, based on available data for a similar substance (THPS) it is expected that THPC may have sensitising properties to skin.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Even if no data are available on THPC for skin sensitisation, a read-across approach done with a similar substance (THPS) is judged relevant for considering the substance of interest as Skin sensitising Category 1 according to CLP regulation (EC) n°1272/2008.