Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity, oral: NOAEL: 2.5 mg/kg bw/day and LOAEL: 5 mg/kg bw/day AI were established, based on liver effects (OECD 408, GLP, Rel. 1).
Repeated dose toxicity, dermal and inhalation: no data was available. Testing is not appropriate due to corrosive properties.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
2.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The studies are GLP compliant with a high quality.

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

1- Repeated dose toxicity: Oral route

The toxicity of the test item Tetrakis [hydroxymethyl] phosphonium chloride oligomeric reaction products with urea and tetradecylamine was evaluated after daily oral administration (gavage) to Wistar Han rats at dose‑levels of 2.5, 5 or 15 mg/kg/day for 13 weeks followed by a 4-week treatment-free period (OECD 408, GLP and reliability: 1).

At all dose-levels, the test item was clinically well tolerated.

At 15 mg/kg/day, adverse microscopic findings were noted in the liver (periportal vacuolar degeneration, hepatocellular hypertrophy and single cell necrosis/apoptosis) of males and females, correlating notably with higher alanine aminotransferase activity in males. These changes were observed to a lesser extent at the end of the treatment-free period, thus suggesting partial reversibility.

Non adverse hypertrophy of cortical cells was observed in the adrenal glands of a few females, correlating with minimally increased adrenal weights. These changes were not seen at the end of the treatment-free period, suggesting total reversibility.

At 5 mg/kg/day, adverse microscopic findings were noted in the liver (periportal vacuolar degeneration, hepatocellular hypertrophy and single cell necrosis/apoptosis) of males, correlating notably with minimally higher alanine aminotransferase activity in this sex.

At 2.5 mg/kg/day, no Adverse laboratory or histopathology changes were observed.

 

Consequently, under the experimental conditions of the study, the No Observed Adverse Effect Level (NOAEL) was established at 2.5 mg/kg/day.

 

2- Repeated dose toxicity: Dermal route

No repeated toxicity study conducted by dermal route was available. However, the waiving is justified on the grounds of animal welfare since THPC-urea-amine is classified in category 1B, H314 (causes severe skin burns and eye damage) according to the CLP regulation (1272/2008) and as corrosive (C, R34) according to the Directive 67/548/EEC.

 

3- Repeated dose toxicity: Inhalation route

No repeated toxicity study conducted by the inhalation route was available. However, the waiving is justified on the grounds of

animal welfare since the substance is classified as corrosive (C; R34/Cat.1; H314). Moreover, handling of the registered substance does not produce vapour, aerosols or droplets.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study performed according to OECD 408 and in compliance with GLP (reliability: 1). The supporting study is an OECD 407.

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

Justification for classification or non-classification

1- Repeated dose toxicity: Oral route

THPC-urea-amine is classified for repeated dose toxicity as STOT RE 1 (H372) according to the criteria of the Regulation (EC) N° 1272/2008 and as T;R48/ R25 according to the criteria of the Directive 67/548/EEC based on:

- The LOAEL /rat (Males + females) - 90 days: 5 mg/kg bw AI/day determined in the key study (liver effects).

 

2- Repeated dose toxicity: Dermal route

No classification is possible due to lack of data

 

3- Repeated dose toxicity: Inhalation route

No classification is possible due to lack of data.