Tetrakis(hydroxymethyl)phosphonium chloride

Endpoint summary

Description of key information

chronic gavage rat LOAEL = 3.75 mg/kg bw/day (liver)
chronic gavage mouse LOAEL = 7.5 mg/kg bw/day (liver)
subchronic gavage rat/mouse NOAEL = 3.75 mg/kg bw/day (liver)
chronic dermal mouse NOAEL = 50 mg/kg bw/day (no systemic effects); NOAEC = 0.25 mg/cm2 (skin irrit)
subchronic dermal rabbit LOAEL = 50 mg/kg bw/day (general bad cond.); LOAEC = 10 mg/cm2 (skin irrit)
subchronic dermal rat LOAEL = 50 mg/kg bw/day (bw loss); LOAEC = 15 mg/cm2 (skin irrit)
repeated dose inhalation: waived
THPC is characterized by primary local toxicity (irritation or corrosion) depending on the concentration applied. The route of exposure is accountable for substance related effects. General systemic effects are considered to be caused by severe and/or repeated local adverse effects.
Systemic toxicity:
Ingestion of THPC in subchronic or chronic studies caused hepatocytic vacuolar degeneration in rats and mice and decreased survival in rats. 
The liver was the organ affected by oral exposure. Subchronic studies: NOEL = 3.75 mg/kg; Chronic studies LOEL = 3.75 mg/kg.
Dermal exposure with THPC in mice caused body weight loss, paralysis of hindleggs and death at doses causing severe skin necrosis.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEL

3.75 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Additional information

Oral subchronic studies: NOEL = 3.75 mg/kg bw/d; hepatocytic vacuolar degeneration. No data on local effects (NTP 1987).

Oral chronic studies: LOEL = 3.75 mg/kg bw/d; hepatocytic vacuolar degeneration in rats. No data on local effects (NTP 1987).

Oral teratogenicicty study: NOAEL = 2 mg/kg bw /day; local changes of gastrointestinal mucosal lining (Clark, 1992).

Dermal chronic: Based on local irritation a MTD of 2 mg THPC/mouse=2 mg/7.5cm2 = 0.25 mg/cm2 (external concentration of 2 mg/0.2mL = 1% in acteon:water (9:1), body surface mouse=75cm2) was identified to be the NOAEC in mice. This corresponds to a NOAEL=50 mg/kg bw/day.

ACGIH, 2005: Although THPC caused local skin irritation in mice, rats and rabbits, there is no evidence to suggest a systemic effect. Hence, a skin notation is not warranted.

Dermal subacute, rabbit: LOAEL (systemic)=50 mg/kg bw/day; LOAEC (local)=17 mg/cm2.

Inhalation chronic (worker), ACGIH 2005: A TLV-TWA of 2 mg/m3 is recommended for THPC which should provide an adequate margin of safety, based on the respective NOAEL in rats of 3.2 mg/kg THPC (equivalent to an inhalation exposure of 22 mg/m3).

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

STOT RE cat 1 H372 (oral gavage, liver) is considered not necessary because of limited exposure under expected normal handling and use. Repeated oral exposure with a corrosive/severe irritating liquid is not a realistic exposure scenario for industrial professionals. In gavage studies, the effective level for systemic effects exceeds the no-effect level for local effects by factor 2.

Repeated dermal exposure studies resulted in local effects. Although THPC caused local skin irritation in mice, rats and rabbits, there is no evidence to suggest systemic toxicity via the dermal route. Hence a skin notation is not warranted (ACGIH 2005).