[1,1':3',1''-Terphenyl]-2'-ol, 5',5''''-(2,2,2-trifluoro-1-methylethylidene)bis-

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: study according to GLP and OECD guideline

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)

Qualifier:

according to guideline

Guideline:

other: US EPA OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Qualifier:

equivalent or similar to guideline

Guideline:

other: US EPA OPPTS 870.3550, Reproduction/Develomental Toxicity Screening Test

GLP compliance:

yes (incl. QA statement)

Remarks:

testing lab.

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: males approx. 11 weeks, females approx. 12 weeks
- Housing: groups of 5 animals of the same sex (pre-mating), females were caged with males on a one-to-one basis (mating), males were housed in home cage at a maximum of 5/cage, females were individually housed (post-mating)
- Diet: ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%):40-70
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

400, specific gravity 1.125

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
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): Based on trial formulations performed at WIL Research Europe
- Amount of vehicle (if gavage): 5ml/kg bw

Details on mating procedure:

- M/F ratio per cage: one-to-one
- Length of cohabitation: max 14 days, up to the detection of sperm in the vaginal smear
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: single

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 (18 February 2015). The concentrations analyzed in the formulations were in agreement with the target concentrations (i.e. mean accuracies between 85% and 115%). The formulations of the high and low dose groups were assessed for homogeneity and were found to be homogenous. Formulations were stable at room temperature for at least 6 hours.

Duration of treatment / exposure:

males: 31 days (2 weeks prior to mating, during mating, and up to the day before necropsy)
females: 40-53 days (2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation); exception: 3 females (1 in group 3 and 2 in group 4) were not dosed on day 21 or 22 post coitum since they were littering at the time of dosing.

Frequency of treatment:

daily

Details on study schedule:

Parental males and females were treated for at least two weeks prior to mating for a maximum of 2 weeks. Males were sacrificed after mating, but not before treatment for at least 28 days. Females were sacrificed after at least 4 days of lactation and were treated continuously up to the day prior to necropsy with the exception of three females which were left untreated for one day because they littered during the treatment time.

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: on the first day of exposure and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on Days 1 and 4. Live pups were weighed on Days 1 and 4 of lactation.

FOOD CONSUMPTION :
Weekly, except for males and females which were housed together for mating and for females without evidence of mating. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and on Days 1 and 4 of lactation.

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of scheduled necropsy
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (overnight)
- How many animals: 5 animals/sex/group
- Parameters examined: white blood cells, differential leukocyte count, red blood cells, reticulocytes, red blood cell distribution width, haemoglobin, haematocrit, MCV, MCH, MCHC, platelets, prothrombin time, activated partial thromboplastin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of scheduled necropsy
- Animals fasted: Yes (overnight)
- How many animals: 5/sex/group
- Parameters examined: ALAT, ASAT, ALP, total protein, albumin, total bilirubin, urea, creatinine, glucose, cholesterol, sodium, potassium, chloride, calcium, inorganic phosphate, bile acids

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: males during week 4 of treatment, females from lactation day 4 onward (before blood sampling)
- Dose groups that were examined: 5 animals/sex/group
- Battery of functions tested: sensory activity / grip strength / motor activity

OTHER:
- pup mortality was determined on day 1 of lactation and daily thereafter.
- cliinical signs for pups were recorded at least once daily
- sex was determined for all pups on days 1 and 4 of lactation

Postmortem examinations (parental animals):

yes, see section 7.5.1 (repeated dose toxicity)

Postmortem examinations (offspring):

Pups surviving to planned termination were killed by decapitation on Days 5-7 of lactation.
All pups were sexed and descriptions of all external abnormalities were recorded. The stomach of pups not surviving to the scheduled necropsy date was examined for the presence of milk, if possible. If possible, defects or cause of death were evaluated.

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

minimal hepatocellular hypertrophy in males

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: Generation: reproductive (migrated information)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

study according to GLP and guideline, Klimisch 1

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A combined repeated dose/reproductive toxicity testing was conducted according to OECD testing guideline 422 (BASF 2015). Male and female rats received daily doses of 0, 100, 300, or 1000 mg/kg bw/d Ligand TFME in polyethylene glycol 400 via gavage (10 animals per sex per dose). Two weeks after start of treatment, males and females of the same dose level were mated on a one-to-one basis for a maximum of two weeks, pairs were separated after verification of mating. Males were analyzed after 31 days continuous treatment, while females were allowed to litter and were sacrificed on postnatal day 5-7 after 40-53 days of continuous treatment. All pups surviving were terminated on Days 5-7 of lactation. All progeny was sexed and external abnormalities were recorded. Parental animals were subjected to gross pathology and organs were fixed and embedded for histopathology (results see section 7.5 – Repeated dose toxicity). Treatment did not result in mortality or signs of systemic toxicity, and no effects on body weight gain or food consumption were observed. The litter sizes and pregnancy rates were comparable between the dose level groups. Gestation index and duration, parturition, maternal care and early postnatal pup development were unaffected by treatment. External macroscopic inspection of progeny did not reveal treatment-related findings. Therefore, the NOAEL for reproductive toxicity, rat, was determined to be ≥1000 mg/kg bw/d.

Short description of key information:
No impact on fertility was observed in an OECD TG 422 study.

Justification for selection of Effect on fertility via oral route:
study according to GLP and guideline

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

The current data do not fulfill the criteria for classification according to Regulation (EC) 1272/2008 or Regulation 67/548/EEC, thus a non-classification for Ligand TFME-DPP is warranted.