Registration Dossier

Administrative data

Endpoint:
neurotoxicity: short-term oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was conducted in compliance with the OECD (1998) and EPA TSCA (1989) Good Laboratory Practices Guidance. (Author)
Cross-reference
Reason / purpose:
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:
other: 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:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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 week ENVIRONMENTAL 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 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 daily/7days per week
Doses / concentrations
Remarks:
Doses / Concentrations:0, 50, 250 and 1000 mg/kg/day Basis:actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Observations and clinical examinations performed and frequency:
Parental animals: Observations and examinations 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 weekly BODY 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 group CLINICAL CHEMISTRY: Yes (males only) - Time schedule for collection of blood: Day 28 - Animals fasted: Yes - How many animals: 5 males per group URINALYSIS: Yes (males only) - Time schedule for collection of urine: Day 28 - Metabolism cages used for collection of urine: Yes
Neurobehavioural examinations performed and frequency:
FUNCTIONAL OBSERVATIONAL BATTERY: Yes - Functional Observational Battery (FOB) including home cage observations, handling observations, open field observations, sensory and neuromuscular observations and physiological observations, was performed on all animals once during quarantine and once per week for F0 animals during prebreed and mating (for both sexes), and during gestation and until lactation Day 21 (F0 females). LOCOMOTOR ACTIVITY: YesAUDITORY STARTLE REFLEX HABITUATION: Yes- Motor activity, auditory startle response and grip strength conducted at study termination (Day 28 for males; Week 8-9 for females)
Sacrifice and (histo)pathology:
All F0 parental animals were necropsied with complete histologic evaluation of 5 selected males and females in the 0 and 1000 mg/kg/day groups.

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
Behaviour (functional findings):
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Description (incidence and severity):
brain and sciatic nerve (F0 animals)
Other effects:
no effects observed
Description (incidence and severity):
Migrated information from 'Further observations for developmental neurotoxicity study'Details on results (for developmental neurotoxicity):F1 Offspring Toxicity Through Weaning (pnd 21):There was no evidence of Fl offspring toxicity either at birth or during lactation. There were no effects on survival indices, litter size, sex ratio/litter, or pup deaths across any groups. Body weights of pups per litter (all pups or separately by sex) were equivalent across all groups for all timepoints, except for significant increases in female and all pup (but not male pup) body weights/litter at 50 mg/kg/day on pnd 0, most likely due to the slightly reduced live litter size (13.1) at this dose relative to the control live litter size (15.8). There were no effects on anogenital distance for either sex at birth. (migrated information)

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male/female
Remarks on result:
other: Generation:
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male/female
Remarks on result:
other: Generation: offspring (migrated information)

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. Reproductive toxicity was not present in F0 males or females. There was also no F1offspring toxicity observed postnatally through the weanling necropsy. Therefore, the F0 male and female systemic no observable adverse effect level (NOAEL) was at or above 1000mg/kg/day for males and females. The NOAELs for F0 reproductive toxicity were observed at or above 1000 mg/kg/day for males and females. The NOAELs for F1 offspring toxicity during lactation were also at or above 1000 mg/kg/day for males and females. (Author)
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, 1000 mg/kg/day to parental FO CD® (SD) rats, 10/sex/group, through prebreed, mating, gestation, and Fl lactation, resulted in essentially no treatment- or dose-related adult FO 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. Reproductive toxicity was not present in FO males or females. There was also no Fl offspring toxicity observed postnatally through the weanling necropsy. Therefore, the FO male (28 days) and female (8 -9 weeks) systemic no observable adverse effect level (NOAEL), including neurotoxicity, was at or above 1000 mg/kg/day. The NOAELs for FO reproductive toxicity were at or above 1000 mg/kg/day for males and females. The NOAELs for Fl offspring toxicity during lactation were also at or above 1000 mg/kg/day for males and females.