Bis(2,4,4-trimethylpentyl)phosphinic acid

Endpoint summary

Description of key information

NOAEL (male, parental toxicity) = 66.7 mg/kg/day based on clinical signs and effects on body weight and food consumption in males from 200.0 mg/kg/day,

NOAEL (female, parental toxicity) = 200 mg/kg/day based on the decrease of the thymus associated with a lymphoid atrophy in females at 600/400 mg/kg/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

66.7 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Recent GLP guideline study (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

In a combined repeated dose toxicity study with the reproductive/developmental toxicity screening test by oral route performed in compliance with the GLP and in accordance with the OECD 422 test guideline, the test substance, diluted in corn oil was administered daily by gavage to Sprague Dawley rats at doses of 0; 66.7; 200 and 600 mg/kg bw/d. The high dose-level group received 600 mg/kg bw/d for 10 days from the beginning of the treatment period only. Because of excessive toxicity at this dose-level (mortality and clinical signs), the high‑dose group was treated at 400 mg/kg bw/d for all the remaining treatment period. Males were exposed 2 weeks before pairing, during pairing and until sacrifice (at least 5 weeks in total) whereas females were exposed 2 weeks before pairing, during pairing, during gestation and during lactation until day 5 post-partum (7-8 weeks in total).

In males, hypoactivity, piloerection, abdominal or loud breathing, eyes half-closed were observed in some animals treated at the dose-levels of 200 and/or 600/400 mg/kgbw/d. In females, hypoactivity, abdominal or loud breathing, eyes half-closed, piloerection, sedation, dyspnea, were observed in some animals treated at the dose-levels of 200 and/or 600/400 mg/kg bw/d. All of these clinical signs recorded from 200 mg/kg/day were considered to be related to the treatment with the test item and of toxicological significance.

There were decreased mean food consumptions from 200 mg/kg bw/d in males only, which correlated with their decreased mean body weights and mean body weight gains. There was a moderate decrease in forelimb grip strength in males and delayed landing foot splay in females at 600/400 mg/kg bw/d which was considered to be related to the treatment with the test item. There was no effect of the test item on hematologic parameters and blood chemistry.

Tubular hyaline droplets were seen with dose-related incidence and severity in some males given the test item at all dose-levels and correlated with increases in relative kidney weights. This was characterized by the presence of dense eosinophilic droplets in proximal tubular epithelium. This effect is not considered as relevant for the human species.

There were statistically significantly higher mean relative weights of liver and adrenals in males given the test item at 200 or 600/400 mg/kg bw/d. Although this was partly due to the decreased body weight (up to -11% at the high-dose), a relationship to the test item could not be completely excluded.

In females given the test item at 600/400 mg/kg bw/d, decreased thymus weights correlated with increased severity of lymphoid atrophy (decreased cellularity and decrease thickness of the cortex and medulla). An effect of the test item could not be excluded for the decreased thymus weights at 600/400 mg/kg bw/d, while the same variations at 200 mg/kg bw/d were considered to be most likely incidental and unrelated to the test item.

Based on the results of this study, 66.7 mg/kg bw/d of test item was established as the no-observed-adverse effect-level (NOAEL) considering the clinical signs and effects on body weight and food consumption observed in males from 200 mg/kg bw/d.

The NOAEL for female parental toxicity was considered to be 200 mg/kg bw/day based on the decrease of the thymus associated with a lymphoid atrophy in females at 600/400 mg/kg bw/d.

Justification for classification or non-classification

According to the CLP Regulation (EC) No 1272/2008 substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement, on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed:

Category 1: 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. Guidance dose/concentration values are provided in 3.9.2.9, to be used as part of a weight-of- evidence evaluation.

Category 2: substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure. 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.

To evaluate whether the substance should be classified or not for specific target organ toxicity-repeated exposure, the available data from a sub-acute study on the substance performed according to the OECD422 Guideline. The NOAEL for male parental toxicity was considered to be 66.7 mg/kg/day based on clinical signs and effects on body weight and food consumption in males from 200.0 mg/kg/day. The NOAEL for female parental toxicity was considered to be 200 mg/kg/day based on the decrease of the thymus associated with a lymphoid atrophy in females at 600/400 mg/kg/day. Considering the NOAEL for male parental toxicity which is the lowest NOAEL determined, it could be considered that the toxic effects observed in the repeated-dose study occur at 200 mg/kg bw/day. However, the NOAEL of male parental toxicity is based on clinical signs and effects on body weight and food consumption in males from 200.0 mg/kg/day; these effects do not to support classification for specific target organ toxicity following repeated exposure (as per the CLP Regulation (EC) No.1272/2008- Annex I: 3.9.2.8). For this reason, NOAEL determined for female parental toxicity (200 mg/kg bw/day) and a LOAEL of 600/400 mg/kg bw/day is considered to for classification purposes; these values were based on the decrease of the thymus associated with a lymphoid atrophy in females at 600/400 mg/kg/day. These levels are determined in a study with a duration of lower than 90 days. Therefore the effect leveles should be extrapolated to equivalent guidance values as the ones indicated in the CLP Regulation (EC) No.1272/2008 - Annex I: 3.9.2.9.6 and Annex I: 3.9.2.9.7. Since these guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats, considering the duration of the current study (males were exposed for a total of 36 days) the guidance values should be multiplied by 2.5.

The substance is therefore not classified for specific organ toxicity following repated exposure according to the CLP Regulation (EC) No.1272/2008