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Endpoint summary

Description of key information

• OECD 422 guideline GLP study (rat, oral gavage)


• OECD 422 guideline GLP study (rat, oral gavage) - Read Across from TDP


• 90-Day repeated dose oral toxicity (OECD 408) (JRF, 2019) - Read Across from TiTDP


• 90-Day repeated dose oral toxicity (males) (LabCorp, 2022) - Read Across from TiTDP

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Species:

rat

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

An OECD 422 guideline GLP study was conducted of tris 2-propylheptyl phosphite.  Groups of 15 male and 15 female Wistar rats were administered the test substance by oral gavage at doses of 0 (corn oil vehicle only), 50, 150 or 450 mg/kg/day.  Doses were administered daily for two weeks prior to mating, and during a two-week mating period. Following mating, males continued on treatment until sacrifice on study day 33.  Females continued on treatment through gestation, parturition, and until sacrifice on lactation day 14.  Two separate groups of 5 male and 5 female animals were treated at the high dose or with corn oil for seven weeks (without mating) and then held for an additional 2 weeks to evaluate the reversibility of any effects. 

Parental animals were evaluated for systemic effects, fertility and reproduction. Litters were culled on Day 4 of lactation and development of the remaining pups evaluated until study termination on lactation day 14.

Treatment-related systemic effects in parental animals were limited to the liver and thyroid. Minimal to mild hepatocellular hypertrophy was seen in 150 and 450 mg/kg b.wt./day males with corresponding liver weight increases at 450 mg/kg b.wt./day.  Clinical chemistry parameters related to liver function (ALT, AST, ALP, GGT, total bilirubin) were similar to control results, therefore, the liver hypertrophy could be considered as an adaptive response.  Similar liver effects were seen in the 450 mg/kg b.wt.\ day females. Mild thyroid follicular cell hypertrophy was seen in 150 and 450 mg/kg b.wt./day males along with corresponding changes in thyroid hormone levels (decreased T3/T4 and increased TSH), and increased thyroid weight at 450 mg/kg b.wt./day.  Similar hypertrophy was seen in 150 and 450 mg/kg b.wt./day females, but without corresponding changes in hormone levels or thyroid weight.

Thyroid gland follicular cell hypertrophy is often seen concomitantly in rats with hepatocellular hypertrophy (adaptive liver changes). In this study, there was dose concordance between the liver and thyroid effects in males, but not in females. 

After the 14-day recovery period, hepatocellular hypertrophy resolved in the males, but not in the females.  Thyroid follicular cell hypertrophy persisted in both males and females.

Given the lack of dose concordance between liver and thyroid effects in females and the persistence of thyroid effects in male and female recovery animals, association of the observed thyroid effects with adaptive changes in the liver was not clearly established. Therefore, a clear systemic NOAEL in parental rats was not established, due to uncertainty about the association between liver and thyroid findings and their significance (adverse or adaptive). The Lowest Systemic Effect Level (LOEL) in parental animals was considered to be 150 mg/kg b. wt./day based on minimal to mild thyroid follicular cell hypertrophy (males and females) and thyroid hormone changes (males only).

In a 28-day dose-range finding study, tris (2-propylheptyl) phosphite administered to Wistar rats by oral gavage produced organ weight effects in liver, thyroid, kidneys and adrenals at 500 and/or 1000 mg/kg b. wt./day.  A follow-up immunohistochemistry evaluation of previously formalin-fixed liver sections from high dose rats did not reveal any notable difference in terms of positivity for catalase (a peroxisome marker) when compared to control rats, though the verification of peroxisome proliferation would warrant the use of more definitive methods.

In a Guideline (modified OECD 422) GLP study with extended treatment to Day 21 of lactation, the structural surrogate TDP administered by gavage once daily at 0, 50, 250 and 1000 mg/kg/day to parental F0 CD (SD) rats, 10/sex/group through prebreed, mating, gestation and F1 lactation resulted in essentially no treatment or dose related adult F0 parental toxicity at any dose at any time. There was no evidence of F0 parental neurotoxicity based on functional observational batteries, motor activity, auditory startle response and grip strength. Therefore, the F0 male (28 days) and female (8 -9 weeks) systemic no observable adverse effect level (NOAEL), including neurotoxicity, was at or above 1000 mg/kg/day for both males and females.

A 90 -day gavage study (OECD 408 by GLP) of the structural surrogate tris isotridecyl phosphite (TiTDP) was conducted in Wistar rats. Groups of 10 male and 10 female animals received daily doses of 42, 125 or 375 mg/kg/day TiTDP, or corn oil (vehicle control). Additional groups of vehicle control and high dose animals were similarly treated and held after treatment to evaluate recovery (28 days for females; 5 or 70 days for males). Animals were evaluated for mortality, clinical signs, body weight, food consumption, neurobehavior, opthalmology, clinical pathology (hematology, clinical biochemistry, urinalysis), organ weights, gross and microscopic pathology. Sperm paramters were also evaluated in male recovery animals. No mortality or morbidity occurred, and no abnormal clinical signs or treatment-related opthalmological or neurobehavioral effects were observed. Body weights and food consumption were comparable to controls. The female NOAEL for TiTDP from this study was 375 mg/kg/day.  The male NOAEL was 125 mg/kg/day based on questionable effects in the testes.  A follow-up 90-day study of TiTDP in male rats was conducted.

In the follow-up study (LabCorp, 2022) of the structural surrogate, TiTDP was administered to male Wistar rats via daily oral gavage at 375 mg/kg/day for either 5, 10 or 13 weeks. Recovery from any effects was evaluated during a 10-week recovery period following 13 weeks of treatment.  Assessment of toxicity was based on mortality, clinical observations, body weights, food consumption, male reproductive tissue assessments, and clinical and anatomic pathology. No TiTDP-related deaths occurred and no TiTDP-related effects were observed on body weights, body weight gains, food consumption.  No TiTDP-related effects were observed in hematology, coagulation, clinical chemistry or urinalysis test results, and no TiTDP-related macroscopic findings were noted in animals at necropsy. TiTDP-related microscopic findings were limited to the liver and included an increased incidence and/or severity of periportal hepatocellular vacuolation (minimal to slight) at the Week 10 and Week 13 sacrifices. These microscopic findings in the liver correlated with increased liver weights; however, no correlating changes were observed in clinical pathology parameters. No TiTDP-related organ weight effects or microscopic findings were noted in any organ/tissue, including the liver, at the recovery sacrifice, consistent with reversibility of liver findings. Microscopic findings in the liver were considered non-adverse. There were no adverse findings in testicular organ weights, testicular histopathology, spermatid concentration, or sperm motility, concentration, or morphology, in animals treated with TiTDP.

The unusual testicular findings of the earlier OECD 408 study (JRF, 2019) were not replicated in this more intensive investigative study (LabCorp, 2022). Based on the more robust results from the repeat study, the subchronic oral no-adverse-effect-level (NOAEL) for TiTDP in the male rat is considered to be 375 mg/kg/day.

Justification for classification or non-classification

In an OECD 422 guideline GLP rat study of tris 2-propylheptyl phosphite, the lowest systemic effect level (subacute LOEL) was considered to be 150 mg/kg b. wt./day based on minimal to mild hepatocellular and thyroid follicular cell hypertrophy (males and females) and thyroid hormone changes (males only). Data on close alkyl phosphite surrogates (triisodecyl phosphite (TDP) and triisotridecyl phosphite (TiTDP) and the hydrolysis product (2-propylheptanol), strongly suggest that these effects are adaptive due to liver induction and liver peroxisome proliferation observed in repeat-dose studies on these chemicals.
The subchronic NOAEL for TiTDP is 375 mg/kg/day. The repeat-dose NOAEL (70-days of exposure) for TDP is 1000 mg/kg/day. These results are considered suitable and reliable for REACH requirements.
Based on the available data, tris 2-propylheptyl phosphite is not classified for repeated dose systemic toxicity under Regulation (EC) 1272/2008.