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EC number: 610-104-3 | CAS number: 43100-47-6
- Life Cycle description
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- Ecotoxicological Summary
- Aquatic toxicity
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- Short-term toxicity to fish
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Endpoint summary
Administrative data
Description of key information
Oral repeated dose administration did not lead to adverse effects in OECD TG 422 study.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- 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 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: US EPA OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents
- 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 oral 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 - 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 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, approximately at the same time each day
- Remarks:
- Doses / Concentrations:
100, 300, 1000 mg/kg bw/d
Basis: - No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on a 14-day dose range finding study, up to 1000 mg/kg bw/d were tested without dose limiting effects
- Observations and examinations performed and frequency:
- 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.
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
- How many animals: 5/sex/group
- Parameters examined: ALAT, ASAT, ALP, total protein, albumin, total bilirubin, urea, creatinine, glucose, cholesterol, sodium, potassium, chloride, calcium, 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
- body weight of live pups was determined on Days 1 and 4 of lactation
- sex was determined for all pups on days 1 and 4 of lactation - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- males at completion of mating period (at least 28 days of dose administration), females which deliver: lactation days 5-7, females which fail to deliver: post-coitum days 25-27
- organ weights: 5 animals/sex/group, adrenal glands, brain, epididymides (all males), heart, kidneys, liver, ovaries, spleen, testes (all males), thymus, uterus (including cervix), prostate (weighed when fixed for at least 24 hours), seminal vesicles including coagulation glands (weighed when fixed for at least 24 hours), thyroid including parathyroid
HISTOPATHOLOGY: Yes
- The following organs were preserved for all animals, and organs and tissues of the selected 5 animals/sex of Groups 1 and 4 were analyzed except for those organs listed in parentheses: adrenal glands, (aorta), brain, caecum,cervix, clitoral gland, colon, coagulation gland, duodenum, epididymides, eyes, mammary gland area, femur including joint, heart, ileum, jejunum, kidneys, liver, lung, lymph nodes, ovaries, (pancreas), peyer's patches, (esophagus), pituitary gland, preputial gland, prostate gland, rectum, (salivary glands), sciatic nerve, seminal vesicles, sceletal muscle, (skin), spinal cord, spleen, sternum, stomach, testes, thymus, thyroid, (tongue), trachea, urinary bladder, uterus, vagina, all gross lesions.
- The additional slides of the testes of all males of Groups 1 and 4 and all males that failed to sire to examine staging of spermatogenesis and histopathology of interstitial cell structure.
- The liver of the selected males of Groups 2 and 3 based on suspected treatment-related microscopic findings in this organ.
- All gross lesions of all animals (all dose groups).
- The reproductive organs (cervix, clitoral gland, coagulation gland, epididymides, ovaries, preputial gland, prostate gland, seminal vesicles, testes, uterus, and viagina) of all animals of Groups 1 and 4 and all males that failed to sire and all females that failed to deliver healthy pups. - Statistics:
- The following statistical methods were used to analyse the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (Ref. 2; many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (Ref. 3; many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test (Ref. 4) was applied to frequency data.
- The Kruskal-Wallis nonparametric ANOVA test (Ref. 5) was applied to motor activity data to determine intergroup differences.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. - 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
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Liver weight was increased in males in dose-dependent manner from 100 mg/kg bw/d.
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Minimal hepatocellular hypertrophy was detected in 2/5 males at 300 mg/kg bw/d and 4/5 males in 1000 mg/kg bw/d
- Histopathological findings: neoplastic:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- 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 guideline and GLP, Klimisch 1
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- 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. The animals were subjected to gross pathology and organs were fixed and embedded for histopathology. Treatment did not result in mortality or signs of systemic toxicity, and no effects on body weight gain, food consumption, hematology or clinical chemistry were observed. Neurological testing did not reveal any differences compared to the control group. The liver weights in males were increased starting at 100 mg/kg bw/d and minimal hepatocellular hypertrophy was detected in 2/5 males at 300 mg/kg bw/d and 4/5 males in 1000 mg/kg bw/d. In the absence of any other signs of toxicity, increased liver weights in males only, together with minimal hepatocellular hypertrophy are considered an adaptive change and are not regarded as adverse effect. Therefore, the NOAEL for subacute repeated dose toxicity, rat, was determined to be ≥1000 mg/kg bw/d.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
study according to guideline and GLP
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.
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