Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 291-813-1 | CAS number: 90480-76-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 05 May 2017 - 03 July 2017
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- designed as dose range finding study
- Deviations:
- yes
- Remarks:
- designed as dose range finding study, thus, only limited ex aminations
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1-[(5-amino-4-methylpentyl)amino]-3-(2-methylphenoxy)-propan-2-ol
- Cas Number:
- 1617528-43-4
- Molecular formula:
- C16H28N2O2
- IUPAC Name:
- 1-[(5-amino-4-methylpentyl)amino]-3-(2-methylphenoxy)-propan-2-ol
- Reference substance name:
- 1,1'-[(2-Methyl-1,5-pentanediyl)diimino]bis[3-(2-methylphenoxy)-propan-2-ol]
- Cas Number:
- 1617528-45-6
- Molecular formula:
- C26H40N2O4
- IUPAC Name:
- 1,1'-[(2-Methyl-1,5-pentanediyl)diimino]bis[3-(2-methylphenoxy)-propan-2-ol]
- Reference substance name:
- Mephenesin
- EC Number:
- 200-427-4
- EC Name:
- Mephenesin
- Cas Number:
- 59-47-2
- Molecular formula:
- C10H14O3
- IUPAC Name:
- 3-(2-methylphenoxy)propane-1,2-diol
- Reference substance name:
- 1,3-bis(2-methylphenoxy)propan-2-ol
- Cas Number:
- 17181-49-6
- Molecular formula:
- C17H20O3
- IUPAC Name:
- 1,3-bis(2-methylphenoxy)propan-2-ol
- Reference substance name:
- 2-methylpentane-1,5-diamine
- EC Number:
- 239-556-6
- EC Name:
- 2-methylpentane-1,5-diamine
- Cas Number:
- 15520-10-2
- Molecular formula:
- C6H16N2
- IUPAC Name:
- 2-methylpentane-1,5-diamine
- Reference substance name:
- 3,3’-(5-(2-hydroxy-3-(o-tolyloxy)propylamino)-4-methylpentylazanediyl)bis(1-(o-tolyloxy)propan-2-ol)
- Molecular formula:
- C36H52N2O6
- IUPAC Name:
- 3,3’-(5-(2-hydroxy-3-(o-tolyloxy)propylamino)-4-methylpentylazanediyl)bis(1-(o-tolyloxy)propan-2-ol)
- Test material form:
- liquid
Constituent 1
Constituent 2
impurity 1
impurity 2
impurity 3
impurity 4
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Wistar Han'": Rccl-lant'': WIST
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS (UK) Ltd., Oxon, UK
- Age at study initiation: time-mated females, delivered prior to day 3 of gestation
- Housing: individually in solid floor polypropylene cage with stainless steel mesh lids and softwood flake bedding
- Diet (e.g. ad libitum): Rodent 2018C Teklad Global Certified Pelleted Diet, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: day of delivery until day 3 of gestation
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- PEG400
- Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure:purchased timed pregnant
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- 17 d (day 3 to 19 of gestation)
- Frequency of treatment:
- daily from day 3 to 19 of gestation
- Duration of test:
- 20 d
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 25 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 75 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- - Time schedule:
mortality: Twice daily, early and late during the working period.
clinical signs: Individual clinical observations will be performed immediately before dosing, up to 30 minutes after dosing and one hour after dosing. In addition, post dosing observations will also be performed at approximately 4 hours after dosing during the normal working day (excluding weekends and Public Holidays). All observations will be recorded.
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights will be recorded on Days 3, 4, 5, 8, 11, 14, 17 and 20 of gestation.
FOOD CONSUMPTION:
Dietary intake will be recorded for individual animals on Days 3, 5, 8, 11, 14, 17 and 20 of gestation.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: Yes
- Time schedule for examinations: Water consumption will be monitored daily by visual inspection of water bottles.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- gross necropsy
- Ovaries and uterine content:
- The uterus of each adult female will be examined and where possible the following recorded;
i. Pregnancy status
ii. Number of corpora lutea
iii. Gravid uterus weight
iv. Number, status* and intra-uterine position of implantations
* = live fetus, dead fetus, late intra-uterine death or early intra-uterine death - Fetal examinations:
- For each fetus/placenta, where possible, the following will be recorded:
i. External fetal abnonnalities
11. Fetal weight
iii. Fetal sex
iv. Placental weight
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Between Day 5 to 7 of gestation, the majority of females treated with 75 or 150 mg/kg bw/day showed instances of increased salivation and/or noisy respiration.
Incidental findings included one 75 mg/kg bw/day females showing observations of deceased respiratory rate, pilo-erection and diarrhoea between Days 5 to 7 with noisy respiration between Days 5 to 10 and 12 to16. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One 150 mg/kg bw/day female was found dead shortly after dosing on Day 5 of Gestation, there were no adverse effects on body weight, food consumption or clinical signs prior to death. Necropsy findings revealed darkened liver and kidneys, with dark patches in the lungs.
There were no further unscheduled deaths on the study. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- All female treatment groups exhibited lower body weight gains following the first dose (Day 3), with improvement evident thereafter.
During the first Week of treatment lower overall accumulative body weight gains were evident in females treated with 75 or 150 mg/kg bw/day in relation to controls. However, during the latter stage of gestation, overall body weight gains return to levels similar to controls. Body weight gains when adjusted for gravid uterus weight, revealed lower body weight gain of 17% and 40%, in females treated with 75 and 150 mg/kg bw/day, respectively. No such effect was detected at 25 mg/kg bw/day. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Instances of marginally lower food consumption were noted in 75 and 150 mg/kg bw/day dose groups between Days 3 to 8 and 3 to 5 of gestation, respectively. Thereafter food consumptions were generally similar to controls.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- Visual inspection of water consumptions revealed no adverse effects.
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- The macroscopic findings in the decedent female (No. 58) findings revealed darkened liver and kidneys, with dark patches in the lungs.
No macroscopic abnormalities were detected in animals examined at study termination. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined - Changes in number of pregnant:
- not examined
- Details on maternal toxic effects:
- Litter Data
There was no detrimental effect of maternal treatment on litter data as assessed by corpora lutea, numbers of implantations, in-utero offspring survival (as assessed by the mean numbers of early or late resorptions), live litter size and sex ratio at 25, 75 or 150 mg/kg bw/day.
Females treated with 150 mg/kg bw/day showed slightly higher pre-implantation losses when compared to controls. Females at 25 or 150 mg/kg bw/day also showed slightly higher post-implantation losses in comparison with controls, without any dose response.
Litter Placental and Foetal weights
There were no effects of maternal treatment on mean foetal weights, placental weights or litter weight at 25, 75 or 150 mg/kg bw/day.
Effect levels (maternal animals)
- Dose descriptor:
- other: upper dose level for definitive OECD TG 422 study
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- mortality
Maternal abnormalities
- Abnormalities:
- not specified
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- not examined
- Visceral malformations:
- not examined
- Details on embryotoxic / teratogenic effects:
- External Examinations
There were no findings apparent for foetuses from treated females at external examination on Day 20 of gestation.
At 150 mg/kg bw/day incidental findings included one litter with five pale fetuses and a further one litter contained one fetus with encephaolcoele.
Effect levels (fetuses)
- Dose descriptor:
- other: upper dose level for definitive OECD TG 422 study
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
Fetal abnormalities
- Abnormalities:
- no effects observed
- Description (incidence and severity):
- only external examinations performed in this dose range finding study
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Bodyweights
Group |
|
Days
|
||||||||||||
|
|
1 |
3 |
4 |
5 |
8 |
11 |
14 |
17 |
20 |
||||
1 |
Mean |
215.0 |
229.0 |
233.8 |
235.0 |
240.8 |
250.0 |
260.5 |
282.5 |
314.3 |
||||
|
SD |
15.4 |
17.2 |
18.5 |
15.7 |
17.5 |
18.6 |
21.0 |
19.8 |
16.5 |
||||
|
n |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
||||
2 |
Mean |
211.0 |
226.6 |
227.2 |
229.8 |
237.8 |
249.6 |
261.0 |
287.4 |
323.2 |
||||
|
SD |
15.6 |
16.6 |
19.1 |
18.6 |
18.6 |
19.4 |
22.1 |
24.0 |
29.4 |
||||
|
n |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
||||
3 |
Mean |
210.0 |
225.2 |
226.6 |
229.8 |
233.2 |
241.0 |
256.2 |
278.0 |
311.6 |
||||
|
SD |
15.2 |
16.2 |
16.3 |
14.5 |
15.2 |
14.4 |
16.3 |
18.3 |
22.6 |
||||
|
n |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
||||
4 |
Mean |
209.8 |
223.0 |
222.3 |
225.8 |
229.0 |
243.3 |
256.3 |
280.3 |
308.0 |
||||
|
SD |
17.8 |
18.8 |
22.1 |
19.0 |
17.6 |
19.5 |
19.6 |
23.3 |
30.5 |
||||
|
n |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
||||
Body weight gains
Group |
|
Days
|
|||||||||||
|
|
1 |
3 |
4 |
5 |
8 |
11 |
14 |
17 |
||||
|
|
3 |
4 |
5 |
8 |
11 |
14 |
17 |
20 |
||||
1 |
Mean |
14.0 |
4.8 |
1.3 |
5.8 |
9.3 |
10.5 |
22.0 |
31.8 |
||||
|
SD |
2.2 |
1.3 |
3.0 |
2.2 |
2.1 |
3.1 |
5.0 |
3.8 |
||||
|
n |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
||||
2 |
Mean |
15.6 |
0.6 |
2.6 |
8.0 |
11.8 |
11.4 |
26.4 |
35.8 |
||||
|
SD |
6.8 |
4.0 |
2.4 |
1.4 |
0.8 |
3.6 |
2.5 |
5.8 |
||||
|
n |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
||||
3 |
Mean |
15.2 |
1.4 |
3.2 |
3.4 |
7.8 |
15.2 |
21.8 |
33.6 |
||||
|
SD |
2.2 |
1.8 |
2.4 |
22.3 |
21.1 |
3.1 |
4.4 |
4.6 |
||||
|
n |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
||||
4 |
Mean |
13.3 |
-0.8 |
3.5 |
3.3 |
14.3 |
13.0 |
24.0 |
27.8 |
||||
|
SD |
4.5 |
3.9 |
3.5 |
2.8 |
2.8 |
2.2 |
3.7 |
8.1 |
||||
|
n |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
||||
Food consumption (g/rat/day)
Group |
|
Days |
|||||
|
|
3 |
5 |
8 |
11 |
14 |
17 |
|
|
5 |
8 |
11 |
14 |
17 |
20 |
1 |
Mean |
16.0 |
14.8 |
18.3 |
21.5 |
19.8 |
22.1 |
|
SD |
1.1 |
3.9 |
1.3 |
2.6 |
2.0 |
1.0 |
|
n |
4 |
4 |
4 |
4 |
4 |
4 |
2 |
Mean |
18.2 |
16.7 |
19.0 |
22.3 |
21.4 |
23.1 |
|
SD |
1.9 |
1.6 |
1.1 |
1.6 |
2.3 |
0.5 |
|
n |
5 |
5 |
5 |
5 |
5 |
5 |
3 |
Mean |
15.1 |
11.6 |
16.9 |
21.3 |
19.7 |
22.5 |
|
SD |
1.7 |
4.7 |
1.3 |
2.4 |
2.1 |
2.6 |
|
n |
5 |
5 |
5 |
5 |
5 |
5 |
4 |
Mean |
12.8 |
14.3 |
17.7 |
21.3 |
19.0 |
19.1 |
|
SD |
1.9 |
1.8 |
1.7 |
2.3 |
2.5 |
3.4 |
|
n |
4 |
4 |
4 |
4 |
4 |
4 |
Group |
|
Copora Lutea |
Number of Implants |
Embryonic/Fetal Deaths |
Implantation losses |
Live young
|
Sex Ratio (% male) |
Mean Fetal Weight
|
Mean Placental Weight |
Litter Weight |
Total Placental Weight |
|||||||
|
Early |
Late |
Total |
Pre- |
Post- |
Male |
Female |
Total |
Male |
Female |
Combined |
|||||||
1 |
Mean |
13.0 |
10.5 |
0.0 |
0.0 |
0.0 |
19.3 |
0.0 |
5.0 |
5.5 |
10.5 |
49.0 |
3.967 |
3.669 |
3.817 |
0.489 |
40.023 |
5.118 |
|
SD |
1.4 |
1.3 |
0.0 |
0.0 |
0.0 |
4.3 |
0.0 |
2.6 |
3.3 |
1.3 |
25.8 |
0.250 |
0.295 |
0.255 |
0.023 |
4.887 |
0.538 |
|
n |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
2 |
Mean |
14.5 |
11.8 |
0.2 |
0.0 |
0.2 |
19.0 |
1.3 |
5.2 |
6.6 |
11.8 |
43.2 |
4.017 |
3.856 |
3.933 |
0.500 |
46.534 |
5.908 |
|
SD |
1.7 |
2.2 |
0.4 |
0.0 |
0.4 |
10.7 |
3.0 |
1.9 |
0.9 |
1.6 |
10.9 |
0.244 |
0.236 |
0.233 |
0.018 |
7.775 |
0.944 |
|
n |
4 |
4 |
5 |
5 |
5 |
4 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
3 |
Mean |
13.0 |
10.2 |
0.0 |
0.0 |
0.0 |
20.8 |
0.0 |
6.0 |
4.2 |
10.2 |
58.1 |
4.381 |
4.165 |
4.297 |
0.538 |
43.648 |
5.448 |
|
SD |
1.9 |
1.6 |
0.0 |
0.0 |
0.0 |
13.7 |
0.0 |
1.6 |
0.4 |
1.6 |
6.9 |
0.196 |
0.248 |
0.194 |
0.078 |
5.933 |
0.937 |
|
n |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
4 |
Mean |
14.5 |
11.0 |
0.3 |
0.0 |
0.3 |
24.7 |
2.5 |
5.3 |
5.5 |
10.8 |
45.2 |
4.462 |
4.176 |
4.281 |
0.565 |
45.493 |
6.153 |
|
SD |
1.3 |
2.9 |
0.5 |
0.0 |
0.5 |
15.0 |
5.0 |
3.6 |
1.0 |
3.1 |
19.5 |
0.402 |
0.474 |
0.447 |
0.123 |
10.959 |
2.402 |
|
n |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
Applicant's summary and conclusion
- Conclusions:
- In consideration of the marked body weight effects on the males during the fourteen day repeated dose phase with non-pregnant animals (Phase I) at 200 mg/kg bw/day and the observed effects on body weight gains on females at 150 mg/kg bw/day during the repeated dose phase on pregnant animals (Phase II), these effects were considered not to be so significant to exclude 150 mg/kg bw/day as the high dose level for further investigating. Therefore, dose levels of 0, 25, 75 and 150 mg/kg bw/day are recommended for the forthcoming Oral (Gavage) Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test in the Rat (OECD 422) (Study No. HD72JH).
- Executive summary:
The purpose of this study was to give a preliminary indication of the effects of repeated oral administration of the test item to rats over a period of fourteen consecutive days (Phase I).
This study was also intended to establish the effects of the test item on the embryonic and fetal development of the rat when administered orally during gestation, including organogenesis (Phase II). The results of the second phase may identify potential effects of the test item on the development of the embryo/fetus in utero. The study was designed to provide toxicological data sufficient to assist in dose level selection for subsequent longer term toxicological evaluation of the test item in the rat and may also provide suitable information to assist in dose level selection for any subsequent oral pre-natal investigation of developmental toxicity (Study No. HD72JH). Clinical observations, body weight changes, food and water consumption and gross pathology will be monitored, for any adverse effects resulting from
exposure to the test item.
In Study Phase I, the test item was administered by oral gavage to three groups, each of five male and five female Wistar Han: RccHan: WIST strain rats, for fourteen consecutive days, at dose levels of 25, 100 and 200 mg/kg bw/day. A control group of five males and five females was dosed with vehicle alone (Polyethylene glycol 400) over the same treatment period.
Clinical signs, body weight development, food consumption and water intake were monitored during the study and all animals were subjected to a gross necropsy examination at termination.
In Study Phase II, the test item was administered once daily by oral gavage to three groups, each of five time-mated Wistar Han: RccHan: WIST strain female rats from Day 3 to Day 19 of gestation at dose levels of 25, 75 and 150 mg/kg bw/day. A control group of five timemated females received vehicle alone (Polyethylene glycol 400) over the same treatment period. All females were killed on Day 20 of gestation.
Clinical signs, body weight development and food consumption were monitored during the study and all animals were subjected to gross necropsy examination including examination of the uterine contents and gross external necropsy of fetuses.
Results
Phase I
Mortality
There were no unscheduled deaths during the study phase.
Clinical Observations
At 200 or 100 mg/kg bw/day animals of either sex exhibited increased post dosing salivation between Days 7 and 13 of treatment.
Body Weight
There were adverse effects on body weight development for animals receiving 200 mg/kg bw/day. No such effects were detected in animals of either sex at 25 or 100 mg/kg bw/day.
Food Consumption
There were reduced food consumptions and food conversion efficiency for animals of either sex at 200 mg/kg bw/day.
Water Consumption
There were no adverse treatment-related effects in water intake compared to controls.
Necropsy
Treatment-related macroscopic findings were confined to enlarged and darkened spleens observed in four 200 mg/kg bw/day females. There were no macroscopic findings in the remaining animals.
Phase II
Mortality
One female dosed with 150 mg/kg bw/day was found dead on Day 5 of gestation, showing no adverse effects prior to the death. Due to this isolated incidence at this dose level the death was considered to be of no toxicological significance.
There were no further unscheduled deaths during Phase II of the study.
Clinical Observations
The majority of females treated with 75 or 150 mg/kg bw/day showed instances of increased salivation and/or noisy respiration.
Body Weight
At 150 or 75 mg/kg bw/day body weight gains and overall accumulated body weight gains showed instances of lower weight gains compared to controls, however, improvement was evident by the end of the treatment period. Body weight gains when adjusted for gravid uterus weight revealed lower group mean body weight gains compared to control at these dose levels.
No such effects were detected at 25 mg/kg bw/day.
Food Consumption
During the first week of treatment dietary intake was generally lower compared to controls at 75 and 150 mg/kg bw/day. However, improvement was evident thereafter.
No such effects were detected at 25 mg/kg bw/day.
Water Consumption
There was no effect evident on water intake at any dose level.
Necropsy
No macroscopic abnormalities were detected in the surviving females.
Litter Data and Placental/Fetal Weights
There were no obvious adverse effects of maternal treatment on litter data as assessed by the number of implantations, early and late embryonic/fetal deaths and live fetuses, or sex ratios as assessed by percentage males.
Fetal Examination
There were no treatment-related findings apparent for fetuses from treated females at external examination of Day 20 of gestation.
Conclusion
Based on the findings of this study, the administration of CGE-PMDA adduct at a dosage of 200 mg/kg bw/day is deemed too high for continued dosing. Although reduced body weight development was observed at 150 mg/kg bw/day with no reproductive effects to treatment, the effects were considered not to be significant enough to dismiss further investigation.
Therefore, dose levels of 25, 75 and 150 mg/kg bw/day are recommended for the forthcoming Oral (Gavage) Combined Repeat Dose Toxicity Study (with Recovery Groups) with Reproduction /Developmental Toxicity Screening Test in the Rat (OECD 422).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.