[No public or meaningful name is available]

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

See Principles of method

Principles of method if other than guideline:

The study exceeded the OECD 422 guideline design by extending dosing of F0 females through Day 21 of lactation (total of 8-9 weeks). The original study design included evaluation of 28 day exposure in females (to correlate with 28 day exposure in males), male and female recovery groups, and extended post weaning evaluation (70 days) in F1 offspring. The final study report contains all sections required by the OECD 422 guideline (1996), including data collected on the FO parental animals and on the Fl offspring to their weaning on pnd 21 (an extension beyond the specified termination on pnd 4 in the OECD 422 [1996] testing guideline). The data collected on the 28-day females, the recovery males and females, and on the F1 offspring animals after weaning were collected as initially specified in the protocol but were not included in the study report. The data not reported (and wet tissues, blocks and slides not processed or examined) were retained in the study records and archived with the study upon the submission of the final report.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triisodecyl phosphite

EC Number:

246-998-3

EC Name:

Triisodecyl phosphite

Cas Number:

25448-25-3

Molecular formula:

C30H63O3P

IUPAC Name:

Phosphorus acid, triisodecyl ester

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): TDP- Analytical purity: > 99%- Lot/batch No.: Doverphos 6, Batch 162T041801

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River Breeding Laboratories, Raleigh, NC- Age at study initiation: 10 weeks- Housing: The animals were individually housed upon arrival, during the acclimation period, and upon the initiation of the treatment period in solid-bottom polycarbonate cages with stainless-steel wire lids (Laboratory Products, Rochelle Park, NJ) with Sani-Chip® cage litter (P.J. Murphy Forest Products Corp., Montville, NJ). Study animals were housed 2 per cage (1 male: 1 female from the same dose group) during the mating period. Females were caged individually once they were successfully mated (or at the end of the mating period) and throughout gestation. Females were housed with their litters throughout the lactation period. Randomly selected Fl weanlings (10/sex/group), males, and females were singly housed during the postweaning exposure period.- Diet (e.g. ad libitum): Pelleted Purina Certified Rodent Diet® (No. 5002, PMI Feeds, Inc., St. Louis, MO was available ad libitum.- Water (e.g. ad libitum): Tap water (source: City of Durham, Department of Water Resources, Durham, NC) was available ad libitum in plastic water bottles with butyl rubber stoppers and stainless-steel sipper tubes.- Acclimation period: 1 weekENVIRONMENTAL CONDITIONS- Temperature (°C): 71.1 to 76.2°F- Humidity (%): 37.2% to 69.6%.- Photoperiod (hrs dark / hrs light): 12-hour light cycle per day

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Male and female CD (Sprague-Dawley(SD)) F0 rats were administered TDP orally by gavage at 0, 50, 250 and 1000 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).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability studies were run on TDP in corn oil at concentrations of 10, 50, and 200 mg/mL (TDP in corn oil). The 50 and 200 mg/mL concentrations were prepared weekly as they were found to be stable. The 10 mg/mL concentration was prepared daily due to stability concerns. Dosage formulations analyzed during the study were found to be 90.8-110% of nominal concentrations.

Duration of treatment / exposure:

F0 males - 28 daysF0 females - 8-9 weeks (14 days prebreed, mating, gestation, lactation through pnd 21)

Frequency of treatment:

once per day

Doses / concentrations

Remarks:

Doses / Concentrations:0, 50, 250 and 1000 mg/kg/dayBasis:actual ingested

No. of animals per sex per dose:

10

Control animals:

yes

Positive control:

No

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes- Time schedule: at least once daily for F0 males and females until necropsy. DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: baseline during quarantine and then weeklyBODY WEIGHT: Yes- Time schedule for examinations: Males - on study Day 0, then weekly and at necropsy; Females - on study Days 0, 7, and 14 (prebreed), and on Gesation Days 0, 7, 14, and 20, and on Lactation Days 0, 4, 7, 14 and 21.FOOD CONSUMPTION: Yes, at the same intervals as body weight.HAEMATOLOGY: Yes- Time schedule for collection of blood: Males - Day 28; Females - Day 13- Animals fasted: Yes- How many animals: 5 per sex per groupCLINICAL CHEMISTRY: Yes (males only)- Time schedule for collection of blood: Day 28- Animals fasted: Yes- How many animals: 5 males per groupURINALYSIS: Yes (males only)- Time schedule for collection of urine: Day 28- Metabolism cages used for collection of urine: YesNEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations: FOB conducted prior to dosing and then weekly unti necropsy. Motor activity, auditory startle response and grip strength conducted at study termination (Day 28 for males; Week 8-9 for females)- Dose groups that were examined: All groups

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, on all animalsHISTOPATHOLOGY: Yes, on 5 control and 5 high dose males and females

Statistics:

The unit of comparison was the male, female, pregnant female, or the litter, as appropriate. Treatment groups were compared to the concurrent control group using either parametric ANOVA under the standard assumptions or robust regression method, which do not assume homogeneity of variance or normality. The homogeneity of variance assumption was examined via Levene's Test. If (p<0.05), robust regression methods were used to test all treatment effects, which use variance estimators that make no assumptions regarding homogeneity of variance or normality of the data. If Levene's Test did not reject the hypothesis of homogeneous variances, standard ANOVA techniques were applied for comparing the treatment groups. The GLM procedure in SAS® Release 8 was used to evaluate the overall effect of treatment and, when a significant treatment effect was present, to compare each exposed group to the control via Dunnett's Test. A one-tailed test (i.e., Dunnett's Test) was used for all pairwise comparisons to the vehicle control group, except that a two-tailed test was used for parental and pup body weight and organ weight parameters, feed consumption, percent males per litter, and anogenital distance. Student's t-test was used for analysis ofbody weight and organ weights from the recovery males and females and the 28-day females. All indices were analyzed by Chi-Square Test for Independence. When Chi-Square revealed significant (p<0.05) differences among groups, then a Fisher's Exact Probability Test, with adjustments for multiple comparisons, w':!s used for pairwise comparisons between each treatment group value and the control group value. Acquisition of developmental landmarks as well as anogenital distance, was also analyzed by Analysis of Covariance. For correlated data SUDAAN® software (RTI, 2001) was used for analysis of overall significance and pairwise comparisons to the control group values.

Results and discussion

Results of examinations

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

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

differences noted are not considered to be adverse based on lack of histopathology and clinical pathology

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

TDP, administered by gavage once daily at 0, 50, 250, 1000 mg/kg/day to parental FO CD® (SD) rats, 10/sex/group, through prebreed, mating, gestation, and lactation, resulted in essentially no treatment- or dose-related adult FO parental toxicity at any dose at any time.

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

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. Therefore, the F0 male (28 days) and female (8-9 weeks) systemic no observable adverse effect level (NOAEL) was at or above 1000mg/kg/day for males and females.

Executive summary:

In a Guideline (modified OECD 422) GLP study with extended treatment to Day 21 of lactation, 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 1000mg/kg/day for both males and females.