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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The reduced pup survival observed at 600.0/400.0 mg/kg/day can be considered as a secondary effect to general findings observed in both sexes from 200 mg/kg/day.

- 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,

- 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,

- NOAEL for reproductive performance (mating and fertility) was considered to be 600.0/400.0 mg/kg/day,

- the NOEL for toxic effects on progeny was considered to be 200.0 mg/kg/day based on the lower viability index on day 4 p.p. at 600.0/400.0 mg/kg/day

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

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

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

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 material, diluted in corn oil was administered daily by gavage to Sprague Dawley rats (10 animals/sex/dose) 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, 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).The animals were paired for mating after 2 weeks of treatment and the dams were allowed to litter and rear their progeny until day 5 p.p.

Animals were checked daily for clinical signs, mortality, and detailed clinical observations were conducted weekly. Body weight was recorded weekly until sacrifice and then at designated intervals throughout gestation and lactation for the females. Female estrous cycle stage was determined each morning during the pairing period, until the females are mated. Prior to sacrifice, blood samples were also taken from these animals for analysis of hematology and blood biochemistry parameters. At sacrifice body weights and selected organs weights were recorded and a complete macroscopic post-mortem examination performed with particular attention paid to the reproductive organs. A microscopic examination was also conducted on selected organs from the first five animals in the control group and the high-dose group. Microscopic examination was conducted on all macroscopic lesions from all groups.

The total litter sizes and numbers of pups of each sex were recorded after birth. The pups were observed daily for clinical signs of toxicity and pup body weights were recorded on days 1 and 5 p.p.

Pups showing relevant external abormalities at scheduled sacrifice and those found dead before study termination, were submitted for a macroscopic post-mortem examination.

At 600 mg/kg bw/d, two males were found dead after treatment on study day 3 or 10 and one male treated at 200 mg/kg bw/d wasprematurely sacrificed on study day 31. Therefore, it has been decided to decrease the dose-level in the high-dose group from 600 to 400 mg/kg bw/d. After macroscopic examination the cause of death of these males was in fact considered to be related to a dosing error. However, clinical signs such as hypoactivity, dyspnea, abdominal breathing and/or reflux in animals of both sexes of the high dose group of 600 mg/kg bw/d justify also this decrease of dosing. In males, 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/kg bw/d. Ptyalism was recorded in almost test item-treated males while hypoactivity was recorded in almost mid- and high-dose groups. In females, 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. Hypoactivity was recorded in some treated females in mid- and high-dose groups and ptyalism was recorded in almost test item treated females. All of these clinical signs recorded from 200 mg/kg bw/day were considered to be related to the treatment with the test item and of toxicological significance. Ptyalism recorded from 66.7 mg/kg/day was also treatment related but considered to be of non-toxicological importance.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.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. Low thymus weights for a single male at 600/400 mg/kg bw/d correlated with marked lymphoid atrophy which was considered to be stress-associated in view of the other inflammatory lesions in this animal.

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.

There were no treatment related effects on mating and fertility data. No relevant differences between control and test item-treated groups were observed regarding the mean duration of gestation, the mean number of corpora lutea, the mean number of implantations, the mean pre-implantation loss, the mean number of pups delivered and the mean post-implantation loss. There was neither effect on the delivery parameters. Furthermore there were no treatment-related effects on live birth and lactation indexes. In the group treated at 600.0/400.0 mg/kg bw/day, the viability index was statistically significantly lower than controls (86.9 % vs.98.6 %, p < 0.001) and an effect of treatment with the test item could not be excluded.

 

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 andeffects 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. There were no adverse effects on the fertility and mating up to the highest tested dose. The NOAEL for progeny was determined to be 200 mg/kg bw/d based on the decrease of the viability index at 600/400 mg/kg bw/d.

Effects on developmental toxicity

Description of key information

NOAEL = 30 mg/kg/day for both maternal parameters and for embryo-fetal development.

At 100 mg/kg/day, in the context of maternal toxicity, the test item treatment was associated with fetal dysmorphogenic potential.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study is GLP compliant and of high quality (Klimisch score = 2)

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

The potential of the substance to cause developmental effects was evaluated in a Read Across approach considering data on Similar substance 01. Justification for Read Across is given in Section 13 of IULCID.

The test substance was daily administered as suspension in corn oil at dose-levels of 10, 30 or 100 mg/kg/day, from Day 6 to Day 20 p.c., by oral route (gavage), to mated female Sprague-Dawley rats.

At 100 mg/kg/day, non adverse excessive salivation and piloerection were observed. A significantly reduced mean body weight gain was recorded between Days 9 and 12 p.c., and between Days 18 and 21 p.c.. Macroscopic findings were observed on stomach and on kidneys, and net body weight change was decreased when compared with controls. Fetal skeletal variations and malformations were observed. At 30 mg/kg/day, macroscopic findings were observed on kidneys, and non adverse fetal skeletal variations were noted. At 10 mg/kg/day, there were no effects of the test item. On the basis of the results obtained in this study, the No Observed Adverse Effect Level (NOAEL) was considered to be 30 mg/kg/day for both maternal parameters and for embryo-fetal development. At 100 mg/kg/day, in the context of maternal toxicity, the test item treatment was associated with fetal dysmorphogenic potential.

Justification for classification or non-classification

Based on the results of the available study, 66.7 mg/kg bw/d of test item was established as the no-observed-adverse effect-level (NOAEL) considering the clinical signs andeffects 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. There were no adverse effects on the fertility and mating up to the highest tested dose. The NOAEL for progeny was determined to be 200 mg/kg bw/d based on the decrease of the viability index at 600/400 mg/kg bw/d.

Based also on the observations in the available study, the registered substance is not classified for reprotoxicity according to the classification criteria of the Regulation (EC) 1272/2008 (CLP).