Triphenyl phosphite

Endpoint summary

Description of key information

Oral: NOAEL = 15 mg/kg bw/d (m/f); rat, according to OECD TG 422, GLP, K2

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

2006

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Remarks:

The information derived from an EPA HPV publication authored by U.S. EPA and no other studies are available for this endpoint. Although only a detailed summary of this study is available, this document is seen as a reliable official publication and thus, graded as K2.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Doverphos 10, Batch 237T03101
Purity 99.7%

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

- Amount of vehicle: 5 ml/kg/day

Duration of treatment / exposure:

- Males: Exposure during premating (2 weeks) and mating (2 weeks)
- Females: Exposure during premating (2 weeks), mating (2 weeks), gestation and lactation (3 weeks)

Frequency of treatment:

daily

Dose / conc.:

5 mg/kg bw/day (actual dose received)

Dose / conc.:

15 mg/kg bw/day (actual dose received)

Dose / conc.:

40 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

Five additional F0 males per group from the control and 40 mg/kg/day groups were designated as recovery animals and held without dosing for 2 weeks after the F0 male dosing period was completed, to evaluate recovery from any possible treatment-related effects identified in the high-dose group.
28-day recovery females (5/group at 0 and 40 mg/kg/day) were similarly assessed.

Observations and examinations performed and frequency:

CLINICAL SIGNS: Yes
- Time schedule: at least once daily

FUNCTIONAL OBSERVATIONAL BATTERY (FOB). Yes
- including home cage observations, handling observations
- Time schedule: On all initial animals once during quarantine and at least once per week for F0 animals during prebreed, mating (both sexes), gestation and lactation (F0 females) treatment periods

Five each of F0 males and females per dose group were evaluated for auditory function, motor activity, and assessment of grip strength prior to necropsy. Grip strength was also assessed for the 5 F1 males and F1 females per group selected for FOB during the last week of the post weaning exposure period.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the prebreed period (F0 males and females), gestation and lactation (F0 females).

FOOD CONSUMPTION: yes
- Time schedule: weekly during the prebreed period (F0 males and females), gestation and lactation (F0 females).

Sacrifice and pathology:

All F0 parental animals and retained F1 adults were necropsied with complete histologic evaluation of 5 selected F0 males and females in the 0 and 40 mg/kg/day groups.

Hematology, clinical biochemistry and urinalysis (males only) were performed at necropsy for 5 randomly selected parental F0 males and females per dose group.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Ataxia, foot splay, with increasing severity

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced body weights, with increasing severity

Dose descriptor:

NOAEL

Effect level:

15 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reduced body weights, ataxia, and foot splay

Critical effects observed:

yes

Lowest effective dose / conc.:

40 mg/kg bw/day (actual dose received)

System:

nervous system

Treatment related:

yes

Conclusions:

The F0 male and female systemic no observable adverse effect (NOAEL) was 15 mg/kg/day.

Executive summary:

This study evaluated the potential of the test item administered by oral gavage one daily, 7 days per week in CD rats, to cause toxic characteristics from repeated dosing, encompassing 2-week prebreed, mating (for both sexes), gestation and lactation (for F0 females) for F0 parents and direct dosing to F1 offspring from weaning to scheduled sacrifice at least 7 weeks post weaning. This study also evaluated the potential of the test substance to cause possible effects on parental male and female reproductive performance (such as gonadal function, mating behavior, conception, development of the conceptus, parturition) and offspring survival, growth, development through lactation, weaning, and through reproductive development until adulthood. This protocol exceeded the OECD 422 study design by following the F1 offspring to adulthood, with continued exposure and assessments of neurologic, immunologic and reproductive structures and functions. The protocol also assessed F0 recovery males, 28-day females and 28day recovery females.

 

Male and female CD (SD) F0 rats were administered orally by gavage at 0, 5, 15 and 40 mg/kg/day at a dose volume of 5 ml/kg/day in Mazola® corn oil, 10 animals/sex/dose for 2 weeks of prebreed exposure (males and females) , 2 weeks of mating (males and females), and 3 weeks of gestation and lactation each (F0 females) for F0 parents, and direct dosing of selected F1 offspring from weaning through scheduled sacrifice , at least 7 weeks post weaning. Five additional F0 males per group from the control and 40 mg/kg/day groups were designated as recovery animals and held without dosing for 2 weeks after the F0 male dosing period was completed, to evaluate recovery from any possible treatment-related effects identified in the high-dose group. Additional 28-day females (5/group at 0 and 40 mg/kg/day) and 28-day recovery females (5/group at 0 and 40 mg/kg/day) were also similarly assessed. Body weights and feed consumption for the F0 males and females were recorded weekly during the prebreed period, for F0 females during gestation and lactation, and for selected F1 offspring from weaning through scheduled sacrifice. Clinical signs were recorded at least once daily for F0 males and females and F1 offspring. Functional Observational Battery (FOB) including home cage observations, handling observations, was performed on all initial animals once during quarantine and at least once per week for F0 animals during prebreed, mating (both sexes) , gestation and lactation (F0 females) treatment periods and on 5 F1 females and 5 F1 males once midway during the post wean exposure period. After the 2-week prebreed exposure period, animals were randomly mated within treatment groups for a 2-week mating period to produce the F1 generation, with continuing exposure. Five each of F0 males and females per dose group were evaluated for auditory function, motor activity, and assessment of grip strength prior to necropsy. Grip strength was also assessed for the 5 F1 males and F1females per group selected for FOB during the last week of the post weaning exposure period.

 

All F0 parental animals, non-selected F1 weanlings and retained F1 adults were necropsied with complete histologic evaluation of 5 selected F0 males and females in the 0 and 40 mg/kg/day groups. Because of extreme toxicity in the F1 offspring at 40 mg/kg/day, no F1 offspring were retained after weaning. Therefore, tissues from 5 F1 males and females per group at 0 and 15 mg/kg/day were examined histopathologically.

 

On the day of birth (postnatal day [pnd] 0), anogenital distance was measured and body weights recorded for all live F1 pups in all litters. F1 litters were culled on pnd 4 to yield as nearly as possible, 5 males and 5 females per litter. The culled F1 pups were weighed, euthanized, and necropsied with complete external and visceral examinations. For the remaining F1 pups, survival indices were calculated at least weekly through weaning (pnd 21). At weaning, at least 1 female and 1 male (whenever possible) from each F1 litter at 0, 5 and 15 mg/kg/day were randomly selected for a total of 10/sex/group to continue treatment for approximately 7 more weeks, with dosing for F1 selected pups begun on pnd 22 until all pups were at least 70 days of age. F1 post weaning observations and procedures for each retained F1 female included examination for vaginal patency (VP, from pnd 22 until acquisition of vaginal opening) and determination of estrous cyclicity and normality evaluated by vaginal smears taken daily the last 3 weeks of the post wean exposure period prior to scheduled sacrifice. For each retained F1 male offspring, observations for cleavage of the balanoprepreputial (preputial separation, PPS) began at 35 days of age and continued until acquisition of PPS. Andrologic assessments were also performed on the F1 retained males at necropsy. Histopathology was performed on F1 males and females (5/sex/group) at 0 and 15 mg/kg/day. In addition, hematology, clinical biochemistry and urinalysis (males only) were performed at necropsy for 5 randomly selected parental F0 males and females and for F1 adult males and females per dose group.

Results
The test substance administered by gavage once daily at 0, 5, 15 and 40 mg/kg/day to parental F0 CD (SD) rats, 10/sex/group, through prebreed, mating and gestation and lactation and direct dosing to the F1 offspring (10/sex/group) from weaning to scheduled sacrifice, resulted in adult F0 parental toxicity at 40 mg/kg/day, increasing over time (reduced body weights, ataxia, and foot splay). Reproductive toxicity was not present in F0 males or females. There was profound F1 offspring toxicity observed postnatally during lactation at 40 mg/kg/day (so the group was terminated on pnd 21) , including increased mortality, especially for pnd 0-4 and reduced pup body weights/litter starting on pnd 7-21. Acquisition of puberty in F1 males and females was unaffected. Twenty eight-day males (same as F0) and females and 28 day recovery males and females exhibited the same progressive systemic toxicity at 40 mg/kg/day as in the F0 parental animals, although the effects were less severe, most likely due to the shorter dosing duration.

The F0 male and female systemic no observable adverse effect (NOAEL) was 15 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

15 mg/kg bw/day

Study duration:

subacute

Species:

rat

System:

nervous system

Organ:

other: Nervous system

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

Repeated dose toxicity oral (subacute)
The available OECD 422 study information are based on an EPA HPV publication authored by U.S. EPA (2006), who published a detailed study summary. As no other studies are available for this endpoint and this this document is a reliable official publication, it is considered to be suitable for classification.

In this GLP compliant repeated dose toxicity study the test item was administered by oral gavage once daily, 7 days per week in CD rats at 5, 15 or 40 mg/kg bw/day (10 animals/sex/group). The administration period encompassed 2-week prebreed, mating (for both sexes), gestation and lactation (for F0 females) for F0 parents. In total, males were dosed 4 weeks while females were dosed 11 weeks. Additionally, the protocol also assessed F0 recovery males, 28-day females and 28-day recovery females.

In adult F0 animals, toxicity was observed at 40 mg/kg/day, increasing over time, including reduced body weights, ataxia, and foot splay. Thus, for F0 a NOAEL of 40 mg/kg/day was established. Based on this findings, the substance is classified as STOT RE 2 for effects on the nervous system. This is supported by the clear neurotoxic effects also observed in neurotoxicity studies in hens upon oral and dermal exposure (see specific investigations).  

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. There were significant toxic effects at doses of less than 300 mg/kg bw upon subacute oral exposure in rats. These consisted primarily of effects on the nervous system at a dosage of 40 mg/kg bw/day. As a result, the substance is considered to be classified for repeated dose toxicity in Category 2 under Regulation (EC) No. 1272/2008, as amended for the fifteenth time in Regulation (EC) No. 2020/1182.