Reaction Products of Diphosphorus Pentaoxide with n-Alcohols, C8-10 (even), salted with Amines, C12-14, Tert-alkyl

Endpoint summary

Description of key information

- 28-day study in rats (OECD 407), doses: 0, 15, 150 and 750 mg/kg bw; NOAEL of 150 mg/kg bw.

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

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study is GLP compliant and is of high quality (Klimisch score of 1).

Additional information

Repeated dose toxicity: oral

In a subacute toxicity study (OECD 407, EU method B7, Japanese MHW guideline) the test item was administered to five Sprague-Dawley strain CD rats/sex/dose by gavage at dose levels of 0, 15, 150, 750 mg/kg bw/day (Wragg et al., 1996).

 

The results are summarised as follows:

 

Mortality: One female dosed at 750 mg/kg/day was killed in extremis on Day 14, due to the severe clinical signs of toxicity observed. There were no further deaths during the study.

 

Clinical Observations: Animals of either sex dosed at 750 mg/kg/day showed increased salivation before or immediately after dosing from Day 1 onwards together with associated fur wetting, red/brown staining of the external body surface and, occasionally, noisy respiration. More prolonged increased salivation was observed from Day 2 and fur loss was evident from the beginning of Week 2 onwards. Sporadic incidents of pilo-erection were also evident amongst animals of either sex during the study. Further clinical observations at this dose level were observed predominantly amongst the females and included hunched posture, diuresis and, less frequently, lethargy, tiptoe gait and chromodacryorrhea. The female decedent showed similar clinical abnormalities to the other females from the same dose group until Day 14, when occasional body tremors were observed towards the end of the working day. This animal was killed in extremis without further treatment. Clinical abnormalities amongst satellite 750 mg/kg/day males regressed immediately following cessation of treatment and females from the same dose group appeared normal in comparison with controls from Day 30 onwards, except for red/brown staining around the ano-genital region.

Animals dosed at 150 mg/kg/day showed short-lived increased salivation immediately after dosing from Day 3 onwards. Two males also showed more prolonged increased salivation during the final two days of treatment. Increased salivation was no longer evident amongst satellite 150 mg/kg/day animals immediately following cessation of treatment.

Animals dosed at 15 mg/kg/day showed no clinically observable signs of toxicity during the study.

 

Bodyweight: Males dosed at 750 mg/kg/day showed a 15% lower bodyweight gain than controls during the first half of the treatment period. There was no adverse effect on bodyweight development amongst these animals during the remainder of the study.

There was no adverse bodyweight effect amongst females dosed at 750 mg/kg/day or amongst animals of either sex from the remaining dose groups that could be attributed to test material toxicity.

 

Food Consumption: Dietary intake was unaffected by treatment with the test material.

Animals of either sex dosed at 750 mg/kg/day showed a slightly reduced food efficiency compared with that of controls during the first half of the treatment-period. There was no adverse effect on food efficiency amongst these animals during the remainder of the study and food efficiency was unaffected by treatment at the remaining dose levels.

 

Water Consumption: Females and, to a lesser extent, males dosed at 750 mg/kg/day showed an increased water intake in comparison with controls during the treatment period. The adverse effect on water intake regressed gradually amongst satellite 750 mg/kg/day following cessation of treatment.

There was no adverse effect on water consumption at the remaining dose levels.

 

Haematology: There were no toxicologically significant changes in the parameters measured.

 

Blood Chemistry: Females dosed at 750 mg/kg/day showed an increased group mean alanine aminotransferase concentration compared with controls. No such change was evident amongst satellite 750 mg/kg/day females following an additional fourteen days without treatment.

Males dosed at 750 mg/kg/day and animals of either sex dosed at 150 or 15 mg/kg/day showed no toxicologically significant changes in the parameters measured.

 

Urinalysis: Three males and one female dosed at 750 mg/kg/day showed a diuresis, producing a copious volume of urine of reduced specific gravity compared with controls. Diuresis was no longer evident amongst satellite 750 mg/kg/day animals following an additional fourteen days without treatment.

Animals dosed at 150 or 15 mg/kg/day showed no toxicologically significant changes in the parameters measured.

 

Organ Weights: Animals of either sex dosed at 750 mg/kg/day showed an increased liver weight, both absolute and relative to terminal bodyweight, in comparison with controls. Males dosed at 750 or 150 mg/kg/day also showed a slightly increased relative kidney weight compared with controls. Satellite 750 mg/kg/day females showed a marginally elevated relative liver weight in comparison with controls following an additional fourteen days without treatment.

Females dosed at 150 mg/kg/day and animals of either sex dosed at 15 mg/kg/day showed no toxicologically significant organ weight changes.

 

Necropsy: Three males dosed at 750 mg/kg/day showed speckled kidneys at terminal kill and one of these animals also showed pale kidneys. No toxicologically significant macroscopic abnormalities were detected amongst satellite 750 mg/kg/day males following an additional fourteen days without treatment.

Females dosed at 750 mg/kg/day, including the animal killed in extremis on Day 14, and animals of either sex from the remaining dose groups showed no toxicologically significant macroscopic abnormalities at necropsy.

 

Histopathology: Animals of either sex dosed at 750 or 150 mg/kg/day showed centrilobular hepatocyte enlargement. Males dosed at 750 or 150 mg/kg/day also showed accumulations of eosinophilic droplets in the renal proximal tubular epithelium. Centrilobular hepatocyte enlargement had mostly regressed amongst satellite 750 or 150 mg/kg/day animals following an additional fourteen days without treatment. Accumulations of eosinophilic droplets in the kidneys showed only partial regression amongst males from either satellite dose group.

Animals dosed at 15 mg/kg/day showed no toxicologically significant morphological lesions.

 

Based on overall effects, water consumption, urinalysis, organ weights, and histopathology, NOAEL is 150 mg/kg bw for both sexes. The NOEL is 15 mg/kg bw/day.

 

This subacute toxicity study in the rat is acceptable and satisfies the guideline requirement for a subacute oral study (OECD 407, EU method B7, Japanese MHW guideline) in the rat.

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

Justification for classification or non-classification

Based on the results of the 28-day study, the substance induced toxicologically significant changes at dose levels of 750 and 150 mg/kg/day. Among organs affected, kidney changes were apparent in males treated with 750 or 150 mg/kg/day, as evidenced by organ weight and histopathological changes. There was, however, no renal dysfunction. Moreover, the test substance is hydrocarbon in nature and this finding is consistent with hydrocarbon nephropathy, which is peculiar to male rats. It is therefore unlikely to occur in humans. Doses of 750 mg/kg/day and 150 mg/kg/day resulted also in liver changes. Histologically, there was evidence of centrilobular hepatocyte enlargement in either sex at both dose levels. In addition, absolute and relative liver weights for either sex were increased at 750 mg/kg/day but not at 150 mg/kg/day. Increased hepatic activity of this type is considered a normal adaptive biological response to a foreign substance and is usually the result of detoxification mechanisms involving hepatic enzyme induction. The adaptive nature of this response was further demonstrated by its reversibility following an additional two weeks without treatment. The slightly raised plasma alanine aminotransferase concentration amongst females dosed at 750 mg/kg/day may indicate a change in hepatocyte membrane permeability not visible by light microscopy. This enzyme was no longer elevated at the end of the fourteen day recovery period. Animals dosed at 15 mg/kg/day showed no toxicologically significant changes in the parameters measured and findings at 150 mg/kg/day were considered not to be indicative of serious damage to the health of the animals, as defined by the labelling criteria given in Directive 93/21/EEC.

In conclusion, classification of this substance is not required for prolonged oral exposure in accordance to EU CLP (Regulation (EC) No. 1272/2008).