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Administrative data

Description of key information

Three key studies of reliability 1 have been identified for the three routes of exposure, the conclusions are the following:
- oral toxicity: LD50/rat = 431 mg/kg bw (expressed as main ingredient; THPS 100%) and LD50/rat = 575 mg/kg bw (expressed as active substance, 75% in water), (OECD 401, Kr.1)
- dermal toxicity: LD50/rat > 1500 mg/kg bw (expressed as main ingredient; THPS 100%) and LD50/rat > 2000 mg/mk bw (expressed as active substance, 75% in water), (OECD 402, Kr.1).
- inhalation toxicity: LC50/rat (aerosol) = 0.443 mg/L (expressed as main ingredient; THPS 100%) and LC50/rat (aerosol) = 0.591 mg/L(expressed as active substance, 75% in water),(OECD 403, Kr.1)

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
575 mg/kg bw
Quality of whole database:
Key study according to OECD 401 with reliability 1.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
0.591 µg/m³
Quality of whole database:
Key study according to OECD 403 with reliability 1.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Key study according to OECD 402 with reliability 1.

Additional information

Acute oral toxicity:

The key study (Guest, 1994a) was performed with THPS 75% in Sprague-Dawley rats according to the EPA OPP 81 -1 (equivalent to OECD Guideline 401) and in compliance with GLP. Five animals/sex/dose were dosed once at three doses 500, 595 and 707 mg/kg bw by gavage (active substance) corresponding to 375, 446 and 530 mg/kg bw as main ingredient by gavage.

The LD50 after 14 days was for the active substance (THPS 75%) 575 mg/kg bw, and for the main ingredient (THPS 100%) = 431 mg/kg bw. Most relevant results were the appearance of the first clinical signs during the first day after dosing, with mainly hunched posture, ataxia and respiratory disturbance. If death had to occur, it was in the first 2 days, otherwise rats recovered a normal behaviour and no anatomical disruption was noticed. Based on this result, THPS (75% and 100%) is considered harmful by oral route.

Acute dermal toxicity:

One study was available and considered as the key study. This study was performed with THPS 75%, in CD rats according to the US EPA Pesticide Assessment Guidelines, Subdivision F, § 81-2 in compliance with the EPA OPPTS 870.1200 and OECD 402 guidelines and in compliance with GLP. Ten animals (5 males and 5 females) were dermally exposed to 2000 mg/kg bw of the test substance (THPS 75%) or 1500 mg/kg bw as main ingredient (THPS 100%) for 24 hours .

No death was observed. Except slight or well-defined temporary erythema observed in two females, no abnormal clinical or anatomical sign was noticed. Results expressed as main ingredient are: LD50> 1500 mg/kg bw, THPS would not have a potential for acute dermal toxicity.

Acute inhalation toxicity:

The acute inhalation toxicity test referenced was performed with THPS in aqueous solution (75.5 %) in Sprague-Dawley rats according to the OECD Guideline 403. This study was not chosen to decide upon the appropriate classification for inhalation; an other study is freely available at the US EPA.

This study was submitted by Cytec Industries Inc. and was accepted by theUScompetent authority. We decided to base the assessment of the acute inhalation toxicity of THPS on this study because:

- It is a GLP study complying with the OECD guideline 403 procedure,

- There is no major difference in the applied method,

- Qualitative description of the toxicological effect (clinical signs, necropsy observations) were similar,

- The aerosolization of the test substance seems to be more relevant in the study produced by Cytec Industries Inc, with more than 70 % of the inhaled particles characterised with an aerodynamic diameter lower or equal to the generally accepted maximum respirable particle size (4µm). While in the Rhodia UK Ltd's study, this proportion falls to 22-26 %,

- The acute inhalation median lethal concentration (LC50) for 4 hour exposure period calculated in the Cytec Industries Inc's study was one order of magnitude lower the value calculated in the study submitted by Rhodia UK Ltd., with 0.591 mg/L and 5.55mg/L respectively.

According to the GLP compliance and the experimental procedure homogeneity (OECD guideline 403) between the studies sponsored by Rhodia UK Ltd. and Cytec Industries Inc., and assuming a possible difference on in the aerosolization process of the test substance and the subsequent effect on the nose only exposure of the rats, the more protective study is chosen for the Human Risk Assessment, that is the study sponsored by Cytec Industries Inc.

Results of this study was as follows; (expressed as main ingredient, considering a typical concentration of 75 %)

Combined sexes: LC50= 0.591 mg/L, THPS as active ingredient is toxic by inhalation (THPS 75%).

In conclusion, acute oral and inhalation exposures to THPS induce common clinical signs of systemic toxicity, with piloerection, ataxia, hunched posture and laboured respiration. Necropsy findings, recorded mainly on animals that died within the observation period after exposure, included coloured/discoloured organs (lung, liver, kidney, digestive tracts). When clinical signs/symptoms of toxicity were observed without any associated adverse pathological findings at necropsy, these affected animals appeared to recover within the observation period following oral dosing but did not all recover completely even following extended observation in the case of inhalation exposure.

Following acute dermal exposure only local dermal effects (erythema) were observed.

THPS 75% is then classified toxic by inhalation, harmful if swallowed, and not hazardous by dermal exposure.


Justification for selection of acute toxicity – oral endpoint
GLP Guideline study with reliability 1. Further studies are available. However, they are considered not valid (Kr. 3).

Justification for selection of acute toxicity – inhalation endpoint
Two key studies of reliability 1 are available. The selected key study was chosen because the results were used to classify THPS 75% in the worst case (see below for more details).

Justification for selection of acute toxicity – dermal endpoint
Only one study was available.

Justification for classification or non-classification

Acute oral toxicity:

- As the LD50/rat/THPS (100%) is 431 mg/kg bw THPS (expressed as main ingredient) is considered as harmful if swallowed and classified into category. 4 (H302) according to the Regulation (EC) 1272/2008 criteria.

- As the LD50/rat/THPS (75% in water) in rat was 575 mg/kg bw (expressed as active substance) is considered as harmful if swallowed and classified into category. 4 (H302) according to the Regulation (EC) 1272/2008 criteria.

Acute dermal toxicity:

- The dermal LD50 for THPS (100%) was > 1500 mg/kg bw. Considering that i) no death nor any toxicity effects was seen during the study with THPS 75% and after post-mortem analysis, ii) dermal absorption is approximately 40 -18 fold lower than oral absorption (depending on dilution) iii) oral LD50 is 431 mg/kg bw (expressed as active ingredient), it can be expected that the dermal LD50 for the active ingredient is higher than 2000 mg/kg bw resulting in no need of classification for this end-point.

- As the combined acute median lethal dose (LD50) of the active substance (THPS 75% in water) in rat was > 2000 mg/kg bw, no classification is required according to EU criteria.

Acute inhalation toxicity:

- As the LC50/4h-aerosol/rat/THPS (100%) is 0.443 mg/L THPS (expressed as main ingredient) is considered as fatal if inhaled and classified into category. 2 (H330) according to the Regulation (EC) 1272/2008 criteria.

- As the LC50/4h-aerosol/rat/THPS (75% in water) is 0.591 mg/L as active substance, THPS (75% in water) is considered as toxic if inhaled and classified into category 3 (H331) according to the Regulation (EC) 1272/2008 criteria.