Tetrakis(hydroxymethyl)phosphonium chloride

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published test report from Nagoya Medical Journal Evaluated data from a reliable secondary source (US-CPSC, 1999; ACGIH, 2005).

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1975

Report date:

1975

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

2000

Reference 3

Reference Type:

secondary source

Title:

Unnamed

Year:

2005

Report date:

2005

Reference 4

Reference Type:

secondary source

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Principles of method if other than guideline:

Rabbits and rats were dosed daily for 20 days with 15%, 20%, or 30% queous solutions of THPC.
Treated animals were continuosly placed under observation even therafter the treatment was discontinued. All animals wer sacrificed after
completion of the experiments and their hematoxylin-eosin stained skin specimens were histological examined.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrakis(hydroxymethyl)phosphonium chloride

EC Number:

204-707-7

EC Name:

Tetrakis(hydroxymethyl)phosphonium chloride

Cas Number:

124-64-1

Molecular formula:

C4H12O4P.Cl

IUPAC Name:

tetrakis(hydroxymethyl)phosphonium chloride

Test animals

Species:

other: rats and rabbits

Sex:

male

Details on test animals or test system and environmental conditions:

88 healthy male white rats of the same strain (bw: 250-300g) were used in a comparative assessment for 7 test items.
30 healthy male white rabbits of the same strain (bw: 3000g) were used in a comparative assessment for 7 test items.

Administration / exposure

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

3 mm portion of the hair from its root was left.
rat: 15%/20%/30% aqueous solutions of THPC (rat: 0.75 ml were applied to 3x3 cm area), corresponding to 450/600/900 mg/kg bw/day (Bittner, CSPC, 1999))
rabbit: 15% and 30% aqueous solutions of THPC (rabbit: 1 ml were applied to 4x4 cm area), corresponding to 50 and 100 mg/kg bw/day (Bittner, CSPC, 1999)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

observation period = treatment period (20 days)

Frequency of treatment:

once a day for 20 consecutive days

No. of animals per sex per dose:

rats: 4 per dose group
rabbits: 2 per dose group

Control animals:

yes, concurrent vehicle

Details on study design:

Protocol amendment: Treatment with THPC were discontinued after day 8 (rats) or after day 6 (rabbit) because of local effects (redness) beginning on day 2 and marked body weight loss. Treated animals were necropsied on day 12 (rats).

Examinations

Observations and examinations performed and frequency:

Rat: Skin reactions beginning on day 2, intensifying till day 6. Falling-off of hair on day 7. The application in rats was discontinued on day 8, but all animals showed marked body weight loss and eventually died on day 9 (high dose group). Surviving animals were necropsied on day 12 (rats).
Rabbit: Redness of skin

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Dermal irritation:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

Rat: Skin reactions beginning on day 2, intensifying till day 6. Falling-off of hair on day 7. The application in rats was discontinued on day 8, but all animals showed marked body weight loss and eventually died on day 9 (high dose group) and were necropsied on day 12 (rats).
Rabbit: Redness of skin on the 2nd day.
Histopathologic findings of the skin: Erythema and epidermal atrophy were observed when rats were treated with 15%, 20%, 30%aqueous THPC (450, 600, 900 mg/kg/day) for 8 days; and all rats of the highest dose group (30% THPC, 900 mg/kg) died after 9 days administration.
When rabbits were treated dermally with a 15% (50 mg/kg/day) THPC solution, severe redness was noted within 6 days; histopathological examination showed subepidermal fibrosis, without the regeneration of papillae, at the 30% concentration (100 mg/kg/day).

Effect levels

1

Dose descriptor:

LOAEL

Remarks:

rat, local

Effect level:

<= 15 mg/cm² per day

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: severe skin effects at site of contact.

2

Dose descriptor:

LOAEL

Remarks:

rat, systemic

Effect level:

<= 450 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: marked body weight loss, death of all high dose animals on day 9 (900 mg/kg bw/day)

3

Dose descriptor:

LOAEL

Remarks:

rabbit, local

Effect level:

<= 17 mg/cm² per day

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: severe skin effects at site of contact

4

Dose descriptor:

LOAEL

Remarks:

rabbit, systemic

Effect level:

<= 50 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: falling-off of hair, treatment discontinued after day 6

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Low dose groups (15% THPC) showed severe local effects in both rats and rabbits.