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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No effects on fertility were observed in a one-generation study on rats and no effects on reproductive organs were reported in recently performed subacute and subchronic toxicity studies on rats. Thus, based on these results, triphenyl phosphate showed no evidence of toxicity to fertility.

A comprehensive assessment of in silico, in vitro and in vivo data on potenial endocrine modulating properties revealed no reliable evidence of a specific and biologically relevant endocrine activity of triphenyl phosphate.

Link to relevant study records

Referenceopen allclose all

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Also assessed by OECD.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Principles of method if other than guideline:
Method: other: see freetext
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
exposure period 91 days
Details on mating procedure:
TPP was administered in the diet for 91 days in a subchronic study. At the completion of this study, females were mated with males from the same group. All remained on the same diet as in the subchronic study until day 20 of gestation when dams were sacrificed.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Exposure period: 91 days
Duration of test: 3 months
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0.25, 0.5, 0.75 or 1 % in feed (= 166, 341, 516, 690 mg/kg)
Basis:
no data
No. of animals per sex per dose:
Four treated groups and an untreated control each consisting of 40 rats/sex
Control animals:
yes, concurrent no treatment
Details on study design:
TPP was administered in the diet for 91 days in a subchronic study. At the completion of this study, females were mated with males from the same group. All remained on the same diet as in the subchronic study until day 20 of gestation when dams were sacrificed.
Parental animals: Observations and examinations:
see below
Oestrous cyclicity (parental animals):
see below
Sperm parameters (parental animals):
no effects
Litter observations:
no effects observed
Postmortem examinations (parental animals):
no adverse effects noted
Postmortem examinations (offspring):
no adverse effects noted
Statistics:
no data
Reproductive indices:
see below
Offspring viability indices:
see below
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
No findings reported. Food consumption increased in pregnant dams (not dose depedant).
Dose descriptor:
NOEL
Effect level:
690 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: no adverse effects were reported
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Histopathological findings:
no effects observed
No adversed effects were observed.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
690 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Examination of the foetuses indicated no effect on body weight, crown-rump length, and sex distribution. There were no external variations or skeletal variations which could be related to TPP exposure.
Critical effects observed:
no
Reproductive effects observed:
no
OBSERVATION: no findings reported
FOOD CONSUMPTION: increased in pregnant dams (not dose-dependent)
BODY WEIGHT: decreased during pregnancy (non-significant)
NECROPSY: no significant differences in number of corpora lutea, implants, implantation efficiency, viable fetuses and number of early or late deaths.
As there was no effect on the litter size (indirectly measured by the number of viable fetuses and implants) and both sexes were treated in the study, these findings indicate that fertility is not adversely affected by TPP in male and female rats.
parental NOEL = 690 mg/kg bw
Conclusions:
Parental NOEL = 690 mg/kg bw
Executive summary:

Fertility and developmental toxicity were examined in a dietary study in Sprague-Dawley rats at doses of 0, 0.25, 0.50, 0.75, 1.0% corresponding to 0, 166, 341, 516 or 690 mg/kg bw/day. Forty males and forty females per group were treated for 3 months and mated afterwards. Animals were treated further throughout mating and gestation and killed at day 20 of gestation.

Effects on fertility- The study included treatment of males and females for three months prior to mating throughout gametogenisis and during mating and gestation. No significant differences were recorded in the number of corpora lutea, implants, implantation efficiency, viable fetuses and the number of early or late deaths between treated and control rats. No significant signs of parental toxicity were detected. As there were no effects on the litter size (indirectly measured by the number of viable fetuses and implants) and both sexes were treated in the study, these findings indicate that fertility is not adversely affected by TPP in male and female rats. The NOEL was 690 mg/kg bw/day.

Endpoint:
fertility, other
Remarks:
other: repeated dose toxicity studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Reason / purpose:
reference to same study
Principles of method if other than guideline:
OECD Guideline 407 and 408 Studies
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 day and 90 day study
Frequency of treatment:
frequently via food
Remarks:
Doses / Concentrations:
up to 508 mg/kg bw/day in male rats and up to 701 mg/kg bw/day in female rats
Basis:
other: 28 day repeated dose toxicity study
Remarks:
Doses / Concentrations:
up to 583 mg/kg bw/day in male rats and up to 632 mg/kg bw/day in female rats
Basis:
other: 90 day repeated dose toxicity study
No. of animals per sex per dose:
5 per sex/dose in the 28 day study and 10 per sex/dose in the 90 day study
Control animals:
yes, concurrent vehicle
Details on study design:
see IUCLID chapter 7.5.1
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
>= 105 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: 90 day repeated dose toxicity study
Remarks on result:
other: Generation not specified
Dose descriptor:
NOAEL
Remarks:
reproductive organ toxicity
Effect level:
>= 583 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: 90 day repeated dose toxicity study
Remarks on result:
other: Generation not specified
Reproductive effects observed:
not specified

Repeated dose toxicity of triphenyl phosphate was investigated in two comprehensive guideline studies performed according to OECD TG 407 and 408 and conducted in compliance with GLP. In the 28 day study the test item was given in dietary concentrations of 0, 250, 1000 or 4000 ppm to 5 male and 5 female Wistar rats per dose group. This corresponds to averaged (over the whole study) test substance intakes of 23, 104 or 508 mg/kg bw/day in males and 39, 161 or 701 mg/kg bw /day in females.

In the 90 day study the test item was given in dietary concentrations of 0, 300, 1500 or 7500 ppm to 10 male and 10 female Wistar rats per dose group. This corresponds to averaged (over the whole study) test substance intakes of 20, 105 or 583 mg/kg bw/day in males and 22, 117 or 632 mg/kg bw /day in females.

The overall NOAEL for repeated dose toxicity is established at 105 mg/kg bw/day based on effects on liver weight in the 90 day study. There were no effects on the weight of the gonads (males: testes and epididymes, seminal vesicles including coagulating glands; females ovaries, uterus including cervix, vagina) or the microscopic examined integrity of the gonads (males: epididymides, prostate, seminal vesicles and testes; females: uterus and ovaries, vagina) at any dose tested.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
583 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Fertility and developmental toxicity were examined in a one-generation dietary study in Sprague-Dawley rats at doses of 0, 0.25, 0.50, 0.75, 1.0% corresponding to 0, 166, 341, 516 or 690 mg/kg bw/day (Welsh et al. 1987). Forty males and forty females per group were treated for 3 months and mated afterwards. Animals were treated further throughout mating and gestation and laparotomy was performed on all females at day 20 of gestation.

No significant signs of parental toxicity were detected. As there were no effects on pregnancy rate, litter size (indirectly measured by the number of viable fetuses and implants), corpora lutea, implants, implantation efficiency, viable foetuses, number of early and late deaths or average percent resorbed. Examination of the foetuses indicated no effect on body weight, crown-rump length, and sex distribution. There were no external variations or skeletal variations which could be related to TPP exposure. On the basis of this one generation reproductive toxicity study TPP has no effect on fertility or developmental toxicity at any dietary concentration tested (Welsh, 1987). The NOEL for reproductive toxicity obtained in this study is 690 mg/kg bw/day.

In a developmental toxicity study on rabbits following OECD 414 with gavage application of triphenyl phosphate in doses of 32, 80 and 200 mg/kg bw/day the external, thoracic and abdominal examination of the dams with special attention being paid to the reproductive organs, showed no macroscopic abnormalities (Peter, 2015).

Repeated dose toxicity of triphenyl phosphate was investigated in two comprehensive guideline studies performed according to OECD TG 407 and 408 and conducted in compliance with GLP. In the 28 day study (Eiben, 2007) the test item was given in dietary concentrations of 0, 250, 1000 or 4000 ppm to 5 male and 5 female Wistar rats per dose group. This corresponds to averaged (over the whole study) test substance intakes of 23, 104 or 508 mg/kg bw/day in males and 39, 161 or 701 mg/kg bw /day in females.

In the 90 day study (van Otterdijk, 2015) the test item was given in dietary concentrations of 0, 300, 1500 or 7500 ppm to 10 male and 10 female Wistar rats per dose group. This corresponds to averaged (over the whole study) test substance intakes of 20, 105 or 583 mg/kg bw/day in males and 22, 117 or 632 mg/kg bw /day in females.

The overall NOAEL for repeated dose toxicity is established at 105 mg/kg bw/day based on effects on liver weight in the 90 day study. The overall NOEL for reproductive toxicity obtained in the repeated dose toxicity studies, based on macroscopic and microscopic evaluations of male and female reproductive organs, is established with the higest dose tested of 583 mg/kg bw/day. There were no effects on the weight of the gonads (males: testes and epididymes, seminal vesicles including coagulating glands; females ovaries, uterus including cervix, vagina) or the microscopic examination of the gonads (males: epididymides, prostate, seminal vesicles and testes; females: uterus and ovaries, vagina) at any dose tested.

In conclusion, no effects on fertility were observed in a one-generation study and no effects on reproductive organs were reported in recently performed subacute and subchronic toxicity studies on rats and a developmental toxicity study on rabbits. Thus, based on these results, triphenyl phosphate showed no evidence of toxicity to fertility. The overall NOEL for reproductive toxicity obtained in fertlity and repeated dose toxicity studies is thus established with 690 mg/kg bw/day.

Triphenyl phosphate (11042-J) is currently within the testing procedure of the National Toxicology Program (NTP) with the following tests:

-       5 days (gavage) toxicity study on Harlan Sprague-Dawley rats (C11042; status: planned)

-       2 week toxicity study on 5 B6C3F1/N mice per sex with doses of 0, 1875, 3750, 7500, or 30000 ppm triphenyl phosphate in food (C20720; status: on test)

-       ‘Modified One-Generation Reproduction Study’ on Harlan Sprague Dawley rats, including neurotoxicology assessment (MOG11042; status for the respective dose-range finding study with administration via food: on test)

-       Toxicogenomics: microarray/analysis (gavage) on Harlan Sprague-Dawley rats (T11042; status: selected)


Assessment of endocrine modulating effects:

A comprehensive literature search was conducted to identify data on potential endocrine modulating properties of triphenyl phosphate. The data was assigned to the OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters levels 1 to 5.

Triphenyl phosphate has a cyclic structure without hydroxyl or amino groups and is thus determined as ‘non-binder to the estrogen receptor’ by the OECD Toolbox Version 3.4.

Triphenyl phosphate showed negative and positive results in some of the screening assays for androgenic and estrogenic activity, but no conclusive picture is given. The activities were seen in general only at cytotoxic concentrations, in the micromolar range and at about 6 magnitudes lower concentrations than triphenyl phosphate detected in human tissues, and are thus not relevant for the in vivo situation. No effects were detected in thyroid related assays. Based on the available information there is no indication of a specific endocrine activity in vitro.

This conclusion is in line with the available animal studies.

In animal studies liver hypertrophy is the most sensitive toxicological effect of triphenyl phosphate with male rats being more susceptible than female rats. The overall NOAEL for repeated dose toxicity is determined with 105 mg/kg bw/day.

There were no gross or microscopic findings to the reproductive system and to reproductive parameters in guideline conform repeated oral dose toxicity studies on rats, in a dermal and developmental toxicity study in rabbits and in a reproduction toxicity study in rats that would point to an endocrine activity of triphenyl phosphate. The NOAEL for reproductive toxicity is determined with 609 mg/kg bw/day in the one-generation study.

Thyroid is affected in male rats by high oral doses of triphenyl phosphate, an effect which is supposed to be secondary to the induced hepatocellular hypertrophy (liver weight increase starting at lower dose in males) and thus not considered to be adverse. This conclusion is supported by in vitro studies that showed no activity of triphenyl phosphate in thyroid related assays.

In conclusion there is no reliable evidence of a specific and biologically relevant endocrine activity of triphenyl phosphate throughout all OECD CF level studies, i.e. in vitro assays and experimental animal studies.

Based on a weight of evidence approach of all available toxicity data triphenyl phosphate is not an endocrine disruptor with respect to human health.

Effects on developmental toxicity

Description of key information

There are no findings indicating any adverse effects on the development of rat fetuses up to the highest tested dose level of 1% in the diet (690 mg/kg bw/day) in rats treated for 3 months prior to mating, throughout mating and up to day 20 of gestation. In a recently performed developmental toxicity study on rabbits (OECD 414) with oral gavage doses of up to and including 200 mg/kg bw/day triphenyl phosphate showed no toxicologically significant effects on maternal and developmental prarmeters investigated. The NOAEL was at least 200 mg/kg bw/day. No higher doses could be tested in pregnant rabbits based on toxicity observed in dose range finding studies.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study.
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Chatillon sur Chalaronne, France
- Nulliparous, non-pregnant and untreated females were used at inititation of the study.
- Age at delivery: 17-19 weeks; mating with adult and proven fertile males at WIL Research
- Fasting period before study: none
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% aqueous solution
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The required amount of test substance was grinded to a fine powder in a grinding mill. Subsequently, the powder was suspended in the vehicle. Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level.

VEHICLE
- Justification for use and choice of vehicle (if other than water): 1% aqueous carboxymethyl cellulose was chosen based on trial formulations performed at WIL.
- Amount of vehicle (if gavage): 5 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses were conducted on a single occasion during the treatment phase (26 November 2014), according to a validated method (Project 506608). Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 6 hours at room temperature was also determined (lowest concentration only).
Details on mating procedure:
After acclimatization, females were housed with sexually mature males (1:1) in special automatic mating cages i.e. with synchronized timing to initiate the nightly mating period, until evidence of copulation was observed. This system reduced the variation in the copulation times of the different females. The females were removed and housed individually if:
a) A copulation plug was observed, and / or
b) The daily vaginal smear was sperm positive.
The day of mating was designated day 0 post coitum.
Male rats of the same source and strain were used only for mating. These male rats are in the possession of RCC and were not considered part of the test system. The fertility of these males had been proven and was continuously monitored.
Duration of treatment / exposure:
Day 6 - 28 post coitum inclusive
Frequency of treatment:
once daily
Duration of test:
All animals surviving to the end of the observation period (Day 29 post-coitum) and the female with premature delivery were euthanised by intravenous injection of pentobarbital (approx. 1 mL/kg Euthasol®20%) and subjected to an external, thoracic and abdominal examination, with special attention being paid to the reproductive organs and the fetuses.
No. of animals per sex per dose:
Each group consisted of 22 mated female rabbits.
Control animals:
yes, concurrent vehicle
Details on study design:
Rationale for dose levels
Dose levels were selected based on the results of a dose range finding study (Project 505943; see APPENDIX 6). In this latter study dose levels of 83, 250 and 750 mg/kgmg/kg bw/day were tested. Due to severe toxicity, all females at 750 mg/kgmg/kg bw/day and one female at 250 mg/kgmg/kg bw/day had to be euthanized before scheduled necropsy. Another female at 250 mg/kgmg/kg bw/day was noted with clinical signs (pale appearance on Days 22 and 23 post-coitum and reduced production of (pale) faeces from Day 17 post-coitum). She had no food consumption from Days 16-23 post-coitum and body weight loss (up to -6%). No signs of toxicity were noted for the remaining females at 250 mg/kgmg/kg bw/day and all females at 83 mg/kgmg/kg bw/day. Based on these data, dose levels of 32, 80 and 200 mg/kgmg/kg bw/day were selected for the present prenatal developmental toxicity study.
Maternal examinations:
Females were checked daily for the presence of clinical signs. Food consumption and body weight were determined at periodic intervals.
All animals surviving to Day 29 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups.
Ovaries and uterine content:
The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated.
Fetal examinations:
External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).

External:
Each viable fetus was examined in detail and weighed. All live fetuses were euthanized by administration of approximately 0.3 mL (= 60 mg) of sodium pentobarbital (Euthasol® 20%; AST Farma B.V., Oudewater, The Netherlands) into the oral cavity using a small flexible plastic or metal feeding tube. Nonviable fetuses (the degree of autolysis was minimal or absent) were examined and weighed. For late resorptions a gross external examination was performed.

Visceral (Internal):
All fetuses were examined for visceral anomalies by dissection in the fresh (non-fixed) state. The thoracic and abdominal cavities were opened and dissected using a technique described by Stuckhardt and Poppe (Ref. 1). This examination included the heart and major vessels. Fetal kidneys were examined and graded for renal papillae development as described by Woo and Hoar. The sex of all fetuses was determined by internal examination.

The heads were removed from approximately one-half of the fetuses in each litter and placed in Bouin's solution (Klinipath, Duiven, The Netherlands). Tissues were then transferred to a 70% aqueous ethanol (Klinipath, Duiven, The Netherlands) for subsequent processing and soft-tissue examination of all groups using the Wilson sectioning technique. After examination, the tissues were stored in 10% formalin. The heads from the remaining one-half of the fetuses in each litter of all groups were examined by a mid-coronal slice.

All carcasses, including the carcasses without heads, were eviscerated, skinned and fixed in identified containers containing 96% aqueous ethanol (Klinipath, Duiven, The Netherlands) for subsequent examination of skeletons.

Skeletal:
The eviscerated fetuses from all groups, following fixation in 96% aqueous ethanol, were macerated in potassium hydroxide (Merck, Darmstadt, Germany) and stained with Alizarin Red S (Klinipath, Duiven, The Netherlands) by a method similar to that described by Dawson. Subsequently, the skeletal examination was done on all fetuses.

The specimens of all groups will be archived in glycerin (Klinipath, Duiven, The Netherlands) with bronopol (Alfa Aesar, Karlsruhe, Germany) as preservative.

A few bones were not available for skeletal examination because they were accidentally damaged or lost during processing. The missing bones were listed in the raw data; evaluation by the fetal pathologist and study director determined there was no influence on the outcome of the individual or overall skeletal examinations, or on the integrity of the study as a whole.
Statistics:
The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control group.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- The Mann Whitney test was used to compare mean litter proportions (percent of litter) of the number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and post-implantation loss, and sex distribution.
- Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test was used to compare the compound-treated groups to the control group.

All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations might be rounded off before printing. Therefore, two groups might display the same printed means for a given parameter, yet display different test statistics values.

No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and post-implantation loss.
Indices:
For each litter the following calculations were performed:

Pre-implantation loss (%) = (number of corpora lutea - number of implantation sites) divided by the number of corpora lutea x 100
Post-implantation loss (%) = (number of implantation sites - number of live fetuses) divided by the number of implantation sites x 100
The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a mean litter proportion on a total group basis, where:

Viable fetuses affected/litter (%) = number of viable fetuses affected/litter divided by the number of viable fetuses/litter x 10
Historical control data:
available
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Gross pathological findings:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): one femaled in the high dose group delivered early
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No toxicologically significant changes were noted in any of the maternal parameters investigated in this study (i.e. mortality, clinical signs, body weights, food consumption, and macroscopic examination) in the tested doses of up to and including 200 mg/kg bw/day. Higher doses were shown to induce strong toxicity (mortality at 750 and 250 mg/kg bw/day) in the dose range finding studies and were thus not included in the main study.
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (actual dose received)
Basis for effect level:
other: developmental toxicity
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Treatment at 200 mg/kg bw/day resulted in a higher incidence of lungs with absent accessory lung lobe(s). While in the control and mid dose groups only one fetus (A015-03 and A048-02, respectively) each was noted with this malformation, the incidence increased to 3(3) fetuses (litter) in the high dose
group (A067-03, A069-07, A074-04). This resulted in a litter proportion of 1.6% which was at the upper limit of the available historical control range for this finding (MAX: 1.7%). In addition, 2 dead fetuses from litter 78 that were delivered preterm on Day 29 post-coitum (A078-03 and A078-05) had absent
accessory lung lobes. The total litter proportion of fetuses at 200 mg/kg bw/day with absent accessory lung lobe(s) thus increased from 1.6% (given in Table 1.15; APPENDIX 1) to 2.4%. This litter proportion was clearly above the range of available historical control data. Lungs with absent accessory lung lobe(s) is a more common finding in New Zealand White rabbits. The historical control data from this laboratory consisted of 17 developmental studies with this strain in which in total 2787 (315) control fetuses (litters) were examined. In 10 of these studies fetuses with absent accessory lung lobe(s) were found, i.e. in total 20 (17) control fetuses (litter). The highest incidence was 3(3) fetuses (litter) seen in 2 studies. As in the high dose group of the present study the incidence of lungs with absent accessory lobe(s) was only slightly higher with in total 5(4) fetuses (litter) including the 2 fetuses from the preterm delivered litter, it was considered as an incidence finding and thus not to be toxicologically relevant.
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
There were no developmental findings up to and including 200 mg/kg bw/day that were considered to be toxicologically relevant.
No toxicologically relevant changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, external, visceral and skeletal developmental malformations or variations, visceral variations). Higher doses were shown to induce strong toxicity (mortality at 750 and 250 mg/kg bw/day) in the dose range finding studies and were thus not included in the main study.
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No toxicologically relevant changes were noted in any of the developmental parameters investigated in this study.
Abnormalities:
not specified
Developmental effects observed:
no

Accuracy, homogeneity and stability of formulations were demonstrated by analyses.

Executive summary:

Triphenyl phosphate was tested in a prenatal developmental toxicity study in pregnant New Zealand rabbits following OECD TG 414. The test item was administered once daily by oral gavage from Days 6 to 28 post-coitum at doses of 0, 32, 80 and 200 mg/kg bw/day in 1% aqueous carboxymethyl cellulose. The doses were chosen on the basis of dose range finding studies that showed strong toxicity (including mortality) at 750 and 250 mg/kg bw/day.

Females were checked daily for the presence of clinical signs. Food consumption and body weight were determined at periodic intervals. Formulations prepared on one day during treatment were analyzed for accuracy, homogeneity and stability.

All animals surviving to Day 29 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. All live fetuses were euthanized. One half of the fetuses were decapitated and the heads were fixed in Bouin’s fixative. All fetuses were dissected and examined for visceral anomalies and subsequently fixed in 96% aqueous ethanol. The fetuses of all groups were stained with Alizarin Red S for skeletal examinations.

No toxicologically significant changes were noted in any of the maternal parameters investigated in this study (i.e. mortality, clinical signs, body weights, food consumption, and macroscopic examination). No toxicologically relevant changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, external, visceral and skeletal developmental malformations or variations, visceral variations).

Based on the results of this prenatal developmental toxicity study, both the maternal and developmental No Observed Adverse Effect Levels (NOAELs) for triphenyl phosphate were established as being at least 200 mg/kg bw/day, since no adverse effect was observed. No higher doses could be tested in pregnant rabbits based on dose range finding studies.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: detailed publication. Also assessed by OECD.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Method: other: see freetext
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: feed
Vehicle:
not specified
Duration of treatment / exposure:
91 days
Frequency of treatment:
daily
Control animals:
yes, concurrent no treatment
Details on study design:
Sex: male/female
Duration of test: 3 months
Maternal examinations:
No adverse effects noted
Ovaries and uterine content:
No adverse effects noted
Fetal examinations:
No significant adverse effects noted
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
>= 690 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 690 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
OBSERVATION: no findings reported
FOOD CONSUMPTION: increased in pregnant dams (not dose-dependent)
BODY WEIGHT: decreased during pregnancy (non-significant)
NECROPSY: no significant differences in number of corpora lutea, implants, implantation efficiency, viable fetuses and number of early or late deaths.
No increase in skeletal anomalies.
Slight, non-dose- related increases in visceral variations
("All treated groups had significantly more fetuses with moderate hydroureter than the control group. However, the high baseline incidence exhibited in the control group and lack of a clear dose-related response make the biological significance of this finding unclear. There were also significantly more fetuses in the treated groups with moderately enlarged ureters in the region adjacent to the kidney than in the controls. Again, the incidence was not related to dose since a greater portion of fetuses were affected in the lower dose levels than in two high levels").
No signs of teratogenicity.
Conclusions:
The NOEL for male and female fertility, maternal toxicity and developmental toxicity was 1% of TPP in the diet (690 mg/kg bw/day).
Executive summary:

Fertility and developmental toxicity were examined in a dietary study in Sprague-Dawley rats at doses of 0, 0.25, 0.50, 0.75, 1.0% corresponding to 0, 166, 341, 516 or 690 mg/kg bw/day. Forty males and forty females per group were treated for 3 months and mated afterwards. Animals were treated further throughout mating and gestation and killed at day 20 of gestation.

Effects on fertility- The study included treatment of males and females for three months prior to mating throughout gametogenisis and during mating and gestation. No significant differences were recorded in the number of corpora lutea, implants, implantation efficiency, viable fetuses and the number of early or late deaths between treated and control rats. No significant signs of parental toxicity were detected. As there were no effects on the litter size (indirectly measured by the number of viable fetuses and implants) and both sexes were treated in the study, these findings indicate that fertility is not adversely affected by TPP in male and female rats. Developmental toxicity- Neither maternal toxicity nor changes in the types or numbers of anomalies in the fetuses were detected. All treated groups had significantly more fetuses with moderate hydroureter than the control group. In the opinion of the authors, the high baseline incidence exhibited in the control group and lack of a clear dose-related response make the biological signficance of this finding unclear. There was also significantly more fetuses in the treated groups with moderately enlarged ureters in the region adjacent to the kidney than in the controls. Again, the incidence was not related to dose since a greater proportion of fetuses having at least two soft-tissue variations was significantly higher than in the 0.25, 0.50 and 0.75 but not the 1% TPP groups than in the control group. The 1% group was only slightly, non-significantly higher than the control. The number of litters with fetuses having at least two soft-tissue variations was significantly greater only in the 0.5 and 0.75% groups. The authors concluded that there was no evidence of bioaccumulation or increased reproductive toxicity after exposure to TPP. The NOEL for male and female fertility, maternal toxicity and developmental toxicity was 1% in the diet (690 mg/kg bw/day). No signs of developmental toxicity were seen up to the highest dose tested.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
other: rat and rabbit
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

Fertility and developmental toxicity were examined in a dietary study in Sprague-Dawley rats at doses of 0, 0.25, 0.50, 0.75, 1.0% corresponding to 0, 166, 341, 516 or 690 mg/kg bw/day. Forty males and forty females per group were treated for 3 months and mated afterwards. Animals were treated further throughout mating and gestation and killed at day 20 of gestation.

Effects on fertility- The study included treatment of males and females for three months prior to mating throughout gametogenisis and during mating and gestation. No significant differences were recorded in the number of corpora lutea, implants, implantation effiiciency, viable fetuses and the number of early or late deaths between treated and control rats. No significant signs of parental toxicity were detected. As there were no effects on the litter size (indirectly measured by the number of viable fetuses and implants) and both sexes were treated in the study, these findings indicate that fertility is not adversely affected by TPP in male and female rats. Developmental toxicity- Neither maternal toxicity nor changes in the types or numbers of anomalies in the fetuses were detected. All treated groups had significantly more fetuses with moderate hydroureter than the control group. In the opinion of the authors, the high baseline incidence exhibited in the control group and lack of a clear dose-related response make the biological significance of this finding unclear. There was also significantly more fetuses in the treated groups with moderately enlarged ureters in the region adjacent to the kidney than in the controls. Again, the incidence was not related to dose since a greater proportion of fetuses having at least two soft-tissue variations was significantly higher than in the 0.25, 0.50 and 0.75 but not the 1% TPP groups than in the control group. The 1% group was only slightly, non-significantly higher than the control. The number of litters with fetuses having at least two soft-tissue variations was significantly greater only in the 0.5 and 0.75% groups. The authors concluded that there was no evidence of bioaccumulation or increased reproductive toxicity after exposure to TPP. The NOEL for male and female fertility, maternal toxicity and developmental toxicity was 1% in the diet (690 mg/kg bw/day). No signs of developmental toxicity were seen up to the highest dose tested.

Triphenyl phosphate was tested in a prenatal developmental toxicity study in pregnant New Zealand rabbits following OECD TG 414 (Peter, 2015). The test item was administered once daily by oral gavage from Days 6 to 28 post-coitum at doses of 0, 32, 80 and 200 mg/kg bw/day in 1% aqueous carboxymethyl cellulose. The dose levels were chosen on the basis of dose range finding studies that showed strong toxicity (including mortality) at 750 and 250 mg/kg bw/day. Females were checked daily for the presence of clinical signs. Food consumption and body weight were determined at periodic intervals. Formulations prepared on one day during treatment were analyzed for accuracy, homogeneity and stability. All animals surviving to Day 29 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. All live fetuses were euthanized. One half of the fetuses were decapitated and the heads were fixed in Bouin’s fixative. All fetuses were dissected and examined for visceral anomalies and subsequently fixed in 96% aqueous ethanol. The fetuses of all groups were stained with Alizarin Red S for skeletal examinations.

No toxicologically significant changes were noted in any of the maternal parameters investigated in this study (i.e. mortality, clinical signs, body weights, food consumption, and macroscopic examination). No toxicologically relevant changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, external, visceral and skeletal developmental malformations or variations, visceral variations). Based on the results of this prenatal developmental toxicity study on rabbits, both the maternal and developmental No Observed Adverse Effect Levels (NOAELs) for triphenyl phosphate were established as being at least 200 mg/kg bw/day, since no adverse effects were observed. No higher doses could be tested in pregnant rabbits based on toxicity in dose range finding studies.

In conclusion, no relevant effects on fetal development were observed in a one-generation study on rats and a developmental toxicity study on rabbits with triphenyl phosphate. The overall NOEL for developmental toxicity is thus established with 200 mg/kg bw/day, the highest dose that could be tested in rabbits.

Justification for classification or non-classification

Triphenyl phosphate showed no effects on fertility or on developmental toxicity in a one generation reproductive toxicity study on rats. Futhermore, in recently performed repeated dose toxicity studies on rats with up to subchronic oral exposure that included macroscopic and microscopic investigations of male and female gonads, the test substance showed no adverse effects on the reproductive organs. In addition, triphenyl phosphate showed no developmental toxicity in a recently performed Guideline study (OECD 414) on rabbits. Thus, the test substance was shown to exert no adverse effects on fertility of male and female rats and on the development of fetuses in pregnant rats and rabbits. According to EU Regulation 1272/2008 no classification for effects on fertility and for effects on developmental toxicity is warranted for triphenyl phosphate.