Triphenyl phosphite

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

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.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

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.

Data source

Reference

Reference Type:

publication

Title:

U.S. EPA HIGH PRODUCTION VOLUME CHEMICAL CHALLENGE PROGRAM - ISODECYLJPHENYL PHOSPHITE CATEGORY

Year:

2006

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Triphenyl phosphite

EC Number:

202-908-4

EC Name:

Triphenyl phosphite

Cas Number:

101-02-0

Molecular formula:

C18H15O3P

IUPAC Name:

triphenyl phosphite

Specific details on test material used for the study:

Doverphos 10, Batch 237T03101
purity 99.7%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

Mazola® corn oil

Details on exposure:

- Amount of vehicle: 5 ml/kg/day

Duration of treatment / exposure:

16 weeks
- Males: Exposure during premating (2 weeks) and mating (2 weeks)
- Females (F0): Exposure during premating (2 weeks), mating (2 weeks), gestation and lactation (3 weeks)
- Exposure of F1 offspring: from weaning to scheduled sacrifice at least 7 weeks post weaning (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.)

Frequency of treatment:

once daily, 7 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

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.
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.

Examinations

Parental animals: Observations and examinations:

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 and on 5 F1 females and 5 F1 males once midway during the post wean exposure period.

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).

Oestrous cyclicity (parental animals):

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.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 10 pups/litter (5/sex/litter as nearly as possible); excess pups were killed

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
Offspring survival, body weight (from weaning until sacrifice), clinical signs (at least once daily), anogenital distance (AGD), pup weight on the day of AGD, development through lactation, weaning, and reproductive development until adulthood

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.

Postmortem examinations (parental animals):

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.

Postmortem examinations (offspring):

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

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 F1 adult males and females per dose group.

- Assessments of neurologic, immunologic and reproductive structures and functions
- Non-selected F1 weanlings were necropsied with complete histologic evaluation of 5 selected F0 males and females in the 0 and 40 mg/kg/day groups.
- The culled F1 pups were weighed, euthanized, and necropsied with complete external and visceral examinations.

Reproductive indices:

reproductive performance (such as gonadal function, mating behavior, conception, development of the conceptus, parturition)

Offspring viability indices:

Survival indices (at least weekly during weaning = post natal day 21)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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

Reproductive function / performance (P0)

Reproductive performance:

no effects observed

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

systemic

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

2

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

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

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Results: F1 generation

General toxicity (F1)

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

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

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

reduced pup body weights/litter starting on pnd 7-21.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

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.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: profound toxicity, including increased mortality and reduced pup body weights/litter

Applicant's summary and conclusion

Conclusions:

The F0 male and female systemic no observable adverse effect (NOAEL) was 15 mg/kg/day. The NOAELs for F0 reproductive toxicity were at or above 40 mg/kg/day for males and females. The NOAELs for F1 offspring toxicity during lactation were 15 mg/kg/day for males and females. The F1 male and female systemic NOAEL was also 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. The NOAELs for F0 reproductive toxicity were at or above 40 mg/kg/day for males and females. The NOAELs for F1 offspring toxicity during lactation were 15 mg/kg/day for males and females. The F1 male and female systemic NOAEL was also 15 mg/kg/day.