Registration Dossier

Administrative data

Description of key information

- By dermal repeated exposure, THPS was too irritating to allow the calculation of a NOAEL/ LOAEL for systemic effects ( OECD 410, Kr.2).
- No data are available on repeated dose toxicity by inhalation, however THPS is not volatile, having very low vapour pressure, and is not supplied for use in aerosol-generating applications.
- By oral route, THPS was studied in rats, mice and dogs in subacute, subchronic and chronic tests.
The key studies for derivation of an oral NOAEL for repeated exposure are 90-day oral studies in the rat (Hill, 1990) and dog (Braun, 2006). Hepatocyte cytoplasmic vacuolation was noted in the portal area of the liver in both species with apoptosis in hepatocytes of the dog only. Raised levels of liver enzymes ALTand AST were also noted in rat studies. The NOAEL derived in both of these studies was 0.75 mg/kg bw/day expressed as main ingredient.

(For more details please read CSR available in section 13).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
0.75 mg/kg bw/day
Study duration:
subchronic
Species:
other: rat and dog.
Quality of whole database:
Repeated dose oral toxicity studies of varying duration from two weeks to 13 weeks, have been carried out in rats, mice and dogs (Kr.2).
The key studies for derivation of an oral NOAEL for repeated exposure are 90-day oral studies in the rat (Hill, 1990) and dog (Braun, 2006). Hepatocyte cytoplasmic vacuolation was noted in the portal area of the liver in both species with apoptosis in hepatocytes of the dog only. Raised levels of liver enzymes ALATand ASAT were also noted in rat studies. 
The NOAEL derived in both of these studies was 0.75 mg/kg bw/day expressed as main ingredient.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral route:

Repeated dose oral toxicity studies of varying duration from two weeks to thirteen weeks, have been carried out in rats, mice and dogs. Data obtained from these studies was consistent with that from studies of a shorter duration and are considered sufficient to assess the chronic toxicity of THPS. Based upon these studies, the principal toxicological effect of THPS active substance consists of microscopic changes in the liver. At high doses, signs of anaemia were observed, based on biochemical and cellular findings. This phenomenon may be related to functional disturbance of the liver and of the bone marrow, in particular with the moderate increase of cellularity of the haematopoietic component. Most of these clinical, biochemical and pathological changes were shown to be reversible following a recovery period in the dog.

The key studies for derivation of an overall NOAEL for this endpoint are 90-day oral studies in the rat (Hill, 1990) and dog (Braun, 2006). Hepatocyte cytoplasmic vacuolation was noted in the portal area of the liver in both species with apoptosis in hepatocytes of the dog only. Raised levels of liver enzymes ALAT and ASAT were also noted in rat studies. The NOAEL derived in both of these studies was 0.75 mg/kg bw/day expressed as main ingredient. 

The mouse was less sensitive to the effects of THPS on the liver, with 90-day NOAEL of 10 mg/kg bw/day (NTP, 1987).

 

Dermal route:

The corrosive properties of THPS on the skin following repeated dermal application precluded derivation of a systemic NOAEL for this route. Due to its low dermal absorption (see Kunz, 2006a in the section 8.8.2), systemic toxicity would not be anticipated at non-irritant concentrations (see Hill, 1989b in the section 8.9.1.3).

 

Inhalation route:

No data are available on repeated dose toxicity by inhalation, however THPS is not volatile, having very low vapour pressure (< 2.6 E-06 hPa at 25 °C, Cowlyn, 1991a, in section 4.6.), and is not supplied for use in aerosol-generating applications. THPS would have no concern with repeated exposure by inhalation.

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: 

The key studies for derivation of an oral NOAEL for repeated exposure are 90-day oral studies in the rat (Hill, 1990) and dog (Braun, 2006). Hepatocyte cytoplasmic vacuolation was noted in the portal area of the liver in both species with apoptosis in hepatocytes of the dog only. Raised levels of liver enzymes ALATand ASAT were also noted in rat studies. 

The NOAEL derived in both of these studies was 0.75 mg/kg bw/day expressed as main ingredient.

Justification for classification or non-classification

Based on the results of all studies cited above, liver effects was observed in rat, mouse and dog. However, these effects were shown to be reversible in the dog study (Braun, 2006). Therefore, no classification is required according to EU criteria.