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Administrative data

Description of key information

LOAEL Tetraphosphorus trisulphide (repeated oral toxicity pregnant female rats treated for 10 days post coitum) = 50 mg/kg bw/day and estimated NOAEL (repeated oral toxicity 28 days rat)= 1 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Test procedure in accordance with generally accepted scientific standards and described in sufficient details.
System:
gastrointestinal tract
Organ:
liver
kidney

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

Mode of Action Analysis / Human Relevance Framework

Additional information

A preliminary prenatal developmental toxicity study was performed to set the doses of the main study OECD TG 422 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test .Each treatment group was composed by 6 mated female rats and they received the test item by oral gavage at the dose levels of 0 (group 1:control), 50 (group 2:low), 100 (group 3: medium-low), 250 (group 4: medium-high) and 500 (group 5: high) mg/kg/day at the beginning of the study. Due to the severe toxicity observed in the high and medium-high dose groups, the dose level of the medium-high group was reduced from 250 to 150 mg/kg/day from Day 5 post coitum of the first batch of mated females. All animals of the high dose group died within 4 days post coitum. The treatment of the medium-high dose group was interrupted on days 6 post coitum and the survival animals were 3. The female rats of the 100 and 50 mg/kg bw/day groups were treated till day 10 post coitum and the survival animals before the interruption of the study were respectively 2 and 4. The post mortem examination revealed macroscopic changes in liver, kidneys and gastric tract starting from dose of 50 mg/kg bw/day. 

Based on the results of the preliminary study OECD TG 422, the LOAEL repeated dose toxicity oral route for Tetraphosphorus trisulphide was set to 50 mg/kg bw/day. This LOAEL was obtained by preliminary test OECD TG 422 performed on pregnant females rats treated for 10 days post coitum. In the main test OECD TG 422 the male and female rats should be treated respectively for about 28 days and for approximately 63 days (at least about 50 days). However, considering the high toxicity observed in preliminary test OECD TG 422 and according to animal welfare legislation, the complete OECD TG 422 on Tetraphosphorus trisulphide was not performed and on precautionary principle NOAEL (repeated oral toxicity 28 days rat)= 1 mg/kg bw/day was chosen to calculate DNEL value. This approach is conservative because, starting from NOAEL =1 mg/kg bw/day, the DNEL value obtained for general population oral route related to long-term exposure is 1.6 μg/kg bw/day, equal to TTC (Threshold of Toxicological Concern) approach 1.5 μg/kg bw/day applied to carcinogenic substances.

Justification for classification or non-classification

According to the CLP Regulation (EC n.1272/2008), classification in category 1 for repeated dose toxicity applies to substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure. Substances are classified in category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations.

 Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations.

 For studies of 28 -day duration, classification in category 1 applies when toxicity by oral route is seen at concentrations below 30 mg/kg bw/day, while category 2 applies for toxicity at doses between 30 and 300 mg/kg bw/day.

 Based on the results of the preliminary study OECD TG 422, the LOAEL Tetraphosphorus trisulphide (repeated oral toxicity pregnant female rats treated for 10 days post coitum) was set to 50 mg/kg bw/day and the substance is classified on precautionary principle H373 (STOT Rep. Exp. 2) according to the CLP Regulation (EC n.1272/2008). The target organs are liver and kidneys.