Octylphosphonic acid

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

12 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The studies are GLP compliant with a high quality (Klimisch score = 1).

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

The study of Hofmann, 1989 is considered as the key study (Kr:1). In this study, octylphosphonic acid was administered in sesame oil to 5 male and 5 female Wistar rats by oral gavage at 0, 12, 60 and 300 mg/kg bw/day for 28 days according to OECD Guideline 407 (1981) and in compliance with GLP. Animals were observed twice daily for mortality and clinical signs. Body weights were recorded before treatment and twice weekly during the study, food consumption was also determined twice weekly, water consumption once a week. Two animals of the high dose group (one male, one female) died on day 28. All other animals survived. Clinical signs noted at 300 mg/kg bw/day included reduced activity, piloerection, hunched posture and irregular respiration. One male showed salivation, while gasping/bad condition was noted in one female. No deaths or clinical signs occurred in the rats of the remaining dose groups. The bodyweight gain of the rats at 300 mg/kg bw/day only was significantly reduced. There were no effects upon the mean daily food and water consumption in the 12 and 60 mg/kg bw/day dose groups while at 300 mg/kg bw/day food consumption was decreased but water consumption was increased. There was an increase in granulocyte and leukocyte count and a decrease of the reticulocyte count at 300 mg/kg bw/day. Creatinine, urea nitrogen and inorganic phosphorus were increased in this dose group. Urine specific gravity was reduced in the high dose group and the urine appeared milky to bright. The urine of two males and three females contained haemoglobin. Absolute and relative kidney weights as well as the relative lung, adrenal and testes weights were increased in the high dose group. Kidneys of animals of the high dose group were enlarged and yellow/brown coloured; the surface of the stomach was crenated and brightened. Adrenals and bone marrow was also brightened. The thymus was reduced. Brightened and enlarged kidneys were also noted in one male and one female of the mid dose group. The histopathological examination of animals of the high dose group showed a massive damage of the kidneys, depression of bone marrow, erosion of the stomach epithelium, and thymus atrophy. In females an increase in haemosiderosis in the spleens was noted. similar findings were also noted in animals of the mid dose group but to a less degree.

Based on the observed severe damage of kidneys, increase of serum urea nitrogen and creatinine, depression of bone marrow and erosion of stomach epithelium observed in rats at 300 mg/kg bw/day and the similar less severe symptoms in the mid dose group, the NOAEL is considered to be 12 mg/kg bw/day.

 

The OECD 421 study, (CIT, 2012) is considered as a supporting study (Kr:1). In this study, OPA was administered to male and female Spargue-Dawley rats, 10/dose/sex, by oral gavage at the dose levels of 0, (vehicle), 12, 30, 80 mg/kg bw/day. The test substance was administered by gavage every day from 14 days prior to the start of mating, until day 5 post-partum for the females and at least for 5 weeks for the males.

At necropsy, A few treatment-related changes were seen at necropsy in kidneys, forestomach and thymus.

Kidney treatment-related changes were seen in both sexes at 80 mg/kg/day, but particularly in females and at 30 mg/kg/day in females. These included tubular necrosis, present in one high-dose group female but mainly basophilia and tubular dilation with peritubular mononuclear cell infiltrate (occasionally associated with a few fibroblasts). Mixed cell infiltrate was seen in papilla in females given 80 mg/kg/day. Granular casts and cellular debris (mix of desquamed and inflammatory cells including granulocytes) were seen in tubules. At 12 mg/kg/day, no treatment-related changes were seen in kidneys. Tubular basophilia was seen at a slightly higher incidence than in the control group, however as this was seen unilaterally and focally, any relationship with the test item was considered to be unlikely at this dose-level.

 

In conclusion, based on the results of the key and a supporting studies, the NOAEL is 12 mg/kg bw/day based on the kidney changes.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The key study was performed according to OECD 407 and in compliance with GLP (reliability: 1). The supporting study is an OECD 421, the parameters required in repeated dose toxicity was not all tested in this study.

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Sub-chronic toxicity study: a testing proposal has been submitted for the OECD 408 study.

Justification for classification or non-classification

Octylphosponic acid is classified for repeated dose toxicity as STOT RE 2 (H373) according to the criteria of the Regulation (EC) N° 1272/2008 based on:

- The LOAEL: 60 mg/kg bw/day determined in the key study (kidneys effects)

- The LOAEL-90d approximately: 15 mg/kg bw/day. In the OECD 421 study, the LOAEL is 30 mg/kg bw/day. In this study, the rats were exposed for more than 40 days (between 40 and 50 days depending on the sexe) which is a longer exposure compared to a subacute toxicity study (28-days). Effects were seen in kidney from the dose of 30 mg/kg bw/day. To extrapolate the LOAEL-90 days, a factor 2 can be applied.