Combined Repeated Dose with Reproduction/Developmental Toxicity

The pdf of this ECHA record is 63 pages, so to help with data extraction, the pdf page numbers where results can be found are indicated for each endpoint/group of endpoints. The pdf contains 3 versions of the methods and results for the same study. The first version is for all systemic endpoints in the parental animals. The second and third versions are for the reproductive and developmental endpoints. The results tables are cut off from full view in the pdf, so the tables will need to be viewed on the ECHA website where you can scroll left and right (click on the full text URL above).

Select Reproductive study type. Do not extract results for recovery control or recovery high groups unless specifically instructed to do so.

P0 endpoints to extract for both P0 male and P0 female groups:

Clinical Observation - description p.5: increase in all treatment groups - use dummy variables

Mortality - description p.5: no treatment related deaths - use dummy variables

Male Body weight and weight gain - table 4 (p.10): for main study group males - extract the means on day 43 and mean body weight gain for days 1-43.

Maternal body weight - table 4 (p.10): extract the means for GD20, LD0, and LD4. It does not appear that the high-dose group was included in the analyses so leave sample size blank for that group.

Food consumption - description p.6: significantly reduced in 100 and 300 mg/kg-day groups - use dummy variables

Hematology, clinical chemistry - table 5 (p.11): extract means for all parameters. Observation time is 42d for all male groups, and LD4 for non-recovery female groups (control, 30, and 100 mg/kg-day). Add a qualitative description of results for recovery females into results notes, such as blood measures are not reported for non-recovery 300 mg/kg-day females on LD4; On day 56, no significant differences were observed in hematology or clinical chemistry for recovery 300 mg/kg-day females.) Also extract blood cholesterol for females at 14d (use dummy variables, description on p.7 indicates significant reductions in all treatment groups).

Urinalysis (evaluated in males only, week 6) - description p.7 indicates no significant changes - use dummy variables

Behavioral tests - best description on p.12; assume 6wk observation timepoint and use dummy variables for all 4 endpoints:

Open field test - ("weekly open field observations did not reveal any treatment-related effects.")
Grip Strength - ("no treatment-related effects were evident for grip or motor activity.")
Motor Activity
Sensory Reactions (EHV 5919) - ("no treatment-related effects were observed")

Gross pathology findings - table 5 (p.11) - extract incidences for small seminal vesicles, small prostate, small testes, small epididymides (description p. 13: "Necropsy - small seminal vessels and prostates observed at 300 mg/kg/day. Small testes and epididymides observed at 100 mg/kg/day. No effects were noted in males at 30 mg/kg/day or females at any treatment level.

Organ weights - table 6 (p.11) - extract all mean organ weights (absolute and relative) for non-recovery males and non-recovery females. Add qualitative description of results for recovery females into results notes, such as organ weights are not reported for non-recovery 300 mg/kg-day females on LD4; On day 56, no significant differences were observed in organ weights for recovery 300 mg/kg-day females vs. recovery control females.

Histopathology findings - descriptions p.8 and p.13 - create endpoints for each lesion/finding described in the text and use dummy variables ("1" for groups with higher incidence or severity compared to control).

Irregular Estrous Cycle - description p.23 use dummy variable and indicate an increase in 300 mg/kg-day females.

Table 7 (p.38-40, description p.23): extract the following endpoints for both male and female groups: mating index (sample size is number that were paired), fertility index (sample size is number mated). "For female animals treated with 300 mg/kg/day, pregnancy was not achieved. A NOAEL was not achieved for reproductive toxicity because of reduced pregnancy rates for parental females treated with 100 and 30 mg/kg/day compared to parental females from the control group." "For male animals, a ‘No Observed Adverse Effect Level’ (NOAEL) could not be established because of infertility at 300 mg/kg/day and reduced fertility at 100 and 30 mg/kg/day."

Table 7 (p.40): gestation index for female groups (sample size is number pregnant)

Pre-coital interval - extract for both males and females - use dummy variables and indicate no effects

Gestation length - extract for females only - use dummy variables and indicate no effects

Table 8 (p.42): means and SDs for corpora lutea, implantation sites, litter size (number of offspring born), live litter size PND0, litter weight PND0

Table 9 (p.44): means and SDs for pre- and post-implantation loss, live birth index

Table 10 (p.45): means and SDs for sex ratio only for at birth. In results notes add comment that there were no significant differences on PND1 or 4.

F1 combined sex group:

Table 8 (p.42): means and SDs litter size PND4, litter weight PND4

Table 9 (p.44): means and SDs viability index (PND4)

Table 12 (p.52): means and SDs Surface righting reflex ("Surface righting assessments on Day 1 post partum did not reveal any significant intergroup differences between litters from treated animals when compared to litters from controls."

F1 endpoints separated by sex:

Table 8 (p.42): means and SDs Pup body weight PND0, PND4, Pup body weight change PND0-4

Clinical Observation (description p.23, table 11): do not extract the findings in Table 11. Instead create 1 endpoint for Clinical Observation, use dummy variables, and indicate no treatment-related findings. ("Daily clinical observations of offspring did not reveal any clinical signs considered to be related to test material toxicity. The clinical signs observed were those commonly observed in offspring in reproductive studies of this type, and were not considered to represent adverse effects of treatment.") Add comment to results notes that specific findings are reported in Table 11.

Necropsy appeared normal (description p.13, table 13): do not extract the findings in Table 13. Instead create 1 endpoint for Necropsy Appeared Normal, use dummy variables, and indicate no treatment-related findings. "No macroscopic abnormalities were detected in offspring."

F1 Female Sprague-Dawley Rats