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Administrative data

Description of key information

90-day oral toxicity study in rat (equivalent or similar to OECD408): - NOAEL: (M) 107.5 mg/kg bw/day, (F) 124.8 mg/kg bw/day (highest doses tested) 21-day dermal toxicity in rabbit  (equivalent or similar to OECD410): - NOAEL: 10 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
107.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

In the key study for the oral route, Phosflex 51B was administered to rats in the diet. No treatment related mortality and clinical signs were noted in the animals. The statistically significant differences in hematology and clinical chemistry values and in red blood cell, plasma and brain cholinesterase activities between control and treated animals were minimal, inconsistent and considered not to be of biological significance. A biologically significant increase in liver and adrenal weights (only females) was noted in the high-dose groups, but this was not regarded as a toxic and therefore not an adverse effect. A NOAEL of 107.5 and 124.8 mg/kg bw/day (equivalent to 1600 ppm) was established for males and females, respectively.

Two supporting studies for the oral route were available: a 28-day and a 90-day toxicity study in rats. The subacute toxicity study (equivalent of established a NOAEL of 250 mg/kg bw/day based on liver effects in all dose groups, except for the lowest dose group. The 90-day toxicity study established a NOAEL of 71.6 mg/kg bw/day and 86.2 mg/kg bw/day for male and female, respectively, based on the absence of effects at the highest dose. The key study was chosen as such as it was performed using the most relevant exposure route (oral versus inhalation), a treatment period of 90 days (as compared to 28-days in the supporting study with a higher NOAEL) and it tested the highest concentration at which no adverse effects were observed (as compared to the other 90-day oral toxicity study).

Two subacute repeated dose toxicity studies for the dermal route are available. In the key study, rabbits were exposed to tBuTPP for 21 days. An evident dose response depression of terminal cholinesterase was observed in the treated males and females, which was significant in the mid and high dose. A NOAEL systemic of 10 mg/kg bw/day was derived. This finding was supported by a second 21 -day study in rabbits, in which a LOAEL systemic of 100 mg/kg bw/day was observed based on the same effects. Due to observed edema and desquamation at the low dose level in the key study, a NOAEL local could not be identified.

Additionally a 90-day inhalation toxicity study in rats was available that established a NOAEL systemic of 101.1 mg/m3 based on the absence of systemic effects at this dose (highest tested). A NOAEL local of 10.1 mg/m3 was established based on local effects on the respiratory system at the highest dose. These effects included rhinitis, sneezing and wheezing.

Justification for classification or non-classification

The most critical NOAEL established for t-BuTPP was 107.5 mg/kg bw/day. When considering the guidance values for classification as outlined in Annex I of 1272/2008/EC (significant effect observed at 100 mg/kg bw/day) and Annex VI of 67/548/EEC (significant effect observed at 50 mg/kg bw/day), the substance does not need to be classified for repeated dose toxicity.