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EC number: 229-175-3 | CAS number: 6422-83-9
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2016-03-21 to 2017-03-03
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2017
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- revised 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3500 (Preliminary Developmental Toxicity Screen)
- Version / remarks:
- July 2000
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1,1'-(4-methyl-1,3-phenylene)bis-1H-pyrrole-2,5-dione
- EC Number:
- 229-175-3
- EC Name:
- 1,1'-(4-methyl-1,3-phenylene)bis-1H-pyrrole-2,5-dione
- Cas Number:
- 6422-83-9
- Molecular formula:
- C15H10N2O4
- IUPAC Name:
- 1,1'-(4-methyl-1,3-phenylene)bis-1H-pyrrole-2,5-dione
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P)14-15 wks
- Weight at study initiation: (P) Males: 371-434 g; Females: 231-290 g
- Housing: individually during premating period for both sexes and during postmating for males depending on mating status, IVC cages (type III H, polysulphone cages)
- Diet (e.g. ad libitum): ad libitum; Altromin 1324 maintenance diet for rats and mice
- Water (e.g. ad libitum): ad libitum, tap water, sulphur acidified to a pH of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals).
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 /12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- PEG 400
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item formulation was prepared once a week based on results obtained from stability investigations. The test item formulation was stored at approximately -20 °C and was thawed at room temperature before each administration.
VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle was selected based on the test item’s characteristics and on results obtained from another study
- Concentration in vehicle: 2, 6 and 12 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required): 57106885543 - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: for maximum 14 days/ until mating
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- DETAILS ON PRETREATMENT
- Sample storage conditions before analysis: After receipt at the Analytics Department samples were stored at -15 to -35°C until analysis. After analysis samples are kept stored at -15 to -35°C until at least 3 months after finalization of phase report.
IDENTIFICATION AND QUANTIFICATION OF TEST SUBSTANCE/PRODUCT
- Separation method (e.g. HPLC, GC): HPLC UV
- Conditions (column, mobile phase, etc.): Column: Atlantis T3 3µm, 3 x 50 mm, Waters 186003721, Nr. 48, Solvent A: Water, Solvent B: Acetonitrile, Injection volume: 6 µL, Flow rate: 0.7 mL/min
- Detection method (e.g. ECD, UV, MS, ICP-AES, ICP-MS): UV
Concentration analysis of formulation samples was determined at three concentrations, 2.0 mg/mL, 6.0 mg/mL and 12.0 mg/mL in study weeks 1, 3, 5 and 7. The mean recoveries observed in the low dose (LD), medium dose (MD) and high dose (HD) groups were 103.7%, 99.7% and 99.5% of the nominal concentration, respectively.
Nominal concentrations were confirmed for all dose groups in study week 1 and study week 7 as measured concentrations were within acceptance criterion of 15%. In study week 3 however, the single samples no.19 (MD) did not meet the acceptance criteria as recovery was lower than 15% of nominal concentration. In study week 5 the single samples no.22 (LD) did not meet the acceptance criteria as recovery was higher than 15% of nominal concentration. These results were verified by reanalysis.
Homogeneity of formulation samples was determined at two concentrations, 2.0 mg/mL and 12.0 mg/mL, in study weeks 1 and 5 of the study. The mean recoveries observed for the LD dose group was 109.1% and 115.3% of the nominal value and 105.2% and 99.2% of the nominal value for HD dose group. The coefficients of variation of the different sampling locations (top, middle, bottom) were 3.1% and 2.0% in LD dose group, 0.4% and 1.3% in HD dose group. All samples were homogenous, as COV was below or equal 15%. - Duration of treatment / exposure:
- Male: 28 days, i.e. 14 days prior to mating and 14 days during mating
Female: maximum 63 days, i.e. 14 days prior to mating, 14 days during mating and during gestation upto postnatal day 12. - Frequency of treatment:
- daily
- Details on study schedule:
- - Age at mating of the mated animals in the study: 16-17 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 30 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 60 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Results of a dose range finding study
- Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- MORTALITY:Yes
- Time schedule: Twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed once before assignment to the experimental groups, on the first day of dosing and weekly thereafter as well as at the end of the study. Females were weighed on gestation day 0, 7, 14 and 20 and within 24 h post partum, i.e., on post partum day 0 and on post partum day 4 and 13 along with their pups.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean weekly diet consumption calculated as g food/week: Yes
Food consumption was measured on the corresponding days of the body weight measurements after the beginning of the dose administration.
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily animals were observed for morbidity and mortality, except on weekends and public holidays when observations were made once daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were made once a day
CLINICAL BIOCHEMISTRY: Yes
- Time schedule: From all dams and 2 pups/litter at termination on day 13 and from all adults males at termination, blood samples were collected from the defined site in serum separator tubes.
- Oestrous cyclicity (parental animals):
- Estrous cycles were monitored before treatment initiation to select for the study females with regular estrous cyclicity. Vaginal smears were also examined daily from the beginning of the treatment period until evidence of mating.
- Sperm parameters (parental animals):
- histopathological examination taking into account the tubular stages of the spermatogenic cycle
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead
CLINICAL BIOCHEMISTRY
From 2 females pups wherever possible/litter on day 4 after birth; from 2 pups/litter at termination on day 13 blood samples were collected from the defined site in serum separator tubes. Subsequently, the blood samples were assessed for serum levels for thyroid hormones (T4). - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals at the end of the mating period, i.e. at day 29 and day 30
- Maternal animals: All surviving animals along with their pups on postnatal day 13
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the thoracic and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [1] were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- Gross necropsy consisted of external and internal examinations including the thoracic and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [1] were prepared for microscopic examination and weighed, respectively.- Statistics:
- A statistical assessment of the results of the body weight, food consumption and absolute and relative organ weights were performed for each gender by comparing values of dosed with control animals of the main groups using a one-way ANOVA and a post-hoc Dunnett Test. These statistics were performed with GraphPad Prism V.6.01 software (p<0.05 was considered as statistically significant).
- Reproductive indices:
- Copulation Index (%) = (No. of rats copulated / No. of pairs) X 100
Fertility Index (%) = (No. of females pregnant / No. of females copulated) X 100
Delivery Index (%) = (No. of dams with live newborns / No. of pregnant dams) X 100
Viability Index (%) = (No. of live offspring at day 4 / No. of live offspring at birth) X 100 - Offspring viability indices:
- No. of Male (live & dead)
No. of Female (live & dead)
Sex ratio (m/f, live & dead)
Live pups
Still birth
Runt
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - no toxicologically relevant clinical signs were noted
- In males, predominant clinical signs observed during the treatment period (PMD 11 to MD 8 ) were diarrhoea in Control (C) and Low Dose (LD) group and both diarrhoea and moving the bedding in Mid Dose (MD) and High Dose (HD) group. Isolated incidences of piloerection, reduced spontaneous activity, abnormal breathing and red nasal discharge in very few male animals of LD, MD and HD.
In females, predominant clinical signs observed during the treatment period (PMD 11 to PND 12 ) were diarrhoea in C and LD group and both diarrhoea and moving the bedding in MD and HD group. Isolated incidences of alopecia on various body parts, pale skin, salivation, vocalisation, piloerection, abnormal breathing, reduced spontaneous activity, wasp waist and red nasal discharge in very few female animals of all groups including control group were considered to be incidental. None of the females showed signs of abortion or premature delivery. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- - no test item-related mortality occurred during the study period.
- During the treatment period of this study, Female no. 44 Control (C) was found dead on premating day (PMD) 13. Female no. 69 (Mid Dose group) was found dead on gestation day (GD) 2.
Male no. 32 High Dose group (HD) was found dead on mating and post mating day (MD) 3. Male no. 35 (HD) was euthanised in moribund condition on PMD 8 due to animal welfare reasons.
Female no. 58 Low Dose group (LD) was euthanised in moribund condition on post-natal day (PND) 0 due to animal welfare reasons. Histopathologically, the cause of death/morbidity in animal no. 32 (HD) and 58 (LD) was considered to be due to gavaging error (tracheal inflammation, thymic inflammation with plant particles). The cause of death/morbidity could not be established for the other animals. - Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- A statistically significant increase in group mean food consumption in female Mid Dose group was observed during premating day 7-14 when compared with the controls. Due to lack of dose dependency and consistency, this statistically significant effect on female food consumption was considered to be incidental and not related to the treatment with test item.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No test item related effect of toxicological relevance was observed on pup thyroid weight and pup thyroxine hormone (T4) in the treatment groups when compared to the controls.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Gross lesions were unremarkable and not related to treatment with the test item.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- The test item had no biologically significant effect on the estrous cycle analyzed during the 2-week premating period after the first administration. There were no considerable differences in the length or sequence of cycle stages between the dose groups and the control group. Deviations from the physiological 4 or 5 day cycle in the rat were observed occasionally in few animals of all treatment groups including control. As this effect was also observed in control animals, it was considered as biological variation and not related to the treatment with the test item.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- Testis weight, epididymis weight and histopathological examination taking into account the tubular stages of the spermatogenic cycle were determined. There were no remarkable effects.
- Reproductive performance:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was a slightly reduced fertility index (number of females pregnant / number of females copulated X 100) of 80 % in the MD group compared to 90 % in all other groups. In the absence of dose response dependency, the finding was not considered to be of toxicological relevance.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- parental toxicity and fertility
- Effect level:
- 60 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: no adverse effect observed up to the highest dose tested
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no test item treatment related effects on litter data including total number of pups born, number of male pups, number of female pups, sex ratio, number of live pups, still births and runts on PND 0 as well as number of male pups, number of female pups, number of live pups and sex ratio on PND 4 and PND 13.
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- A marginally higher mean mortality of pups between PND 4 and PND 13 was observed in the HD group (1.01%) compared to the control group (0.00%). This outcome did not achieve statistical significance and was attributed to missing one single pup of one
single dam (pup no. 2 of dam no. 78) on PND 8. This effect was considered as incidental and not related to the treatment with the test item. There were also few mortalities/missing pups observed from LD and MD group, and as a result a higher mean mortality of pups between PND 0 and PND 4 was observed in the LD and MD groups (2.81 and 0.89 %, respectively) compared to the control group (0.00%). Due to lack of dose dependency and consistency, this effect in LD and MD group was not considered to be treatment related. - Body weight and weight changes:
- no effects observed
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Description (incidence and severity):
- No test item related effect of toxicological relevance was observed on anogenital distance and nipple retention in the pups of any of the groups. However, statistically significantly lower male pup weight, cube root of male pup weight and relative anogenital distance of male pups was observed in MD group when compared with the controls. Due to lack of dose dependency and consistency, this effect in MD group was not considered to be treatment related.
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No test item related gross external abnormalities of toxicological relevance on PND 0 were observed in the pups of any of the groups.
Few specific findings like wound on left knee on PND 2 (pup no 10 from dam 54) and dark scruff on PND 0 (pup no. 7 from dam 54) were observed in LD group. Female number 58 from LD group was euthnaised for animal welfare reasons on PND 0 after littering and 10 out of 12 pups were still born and other 2 pups were euthanised with dam due to welfare reasons. On PND 0, these pups were observed with predominant external findings like dark head, bloody mouth and few were partly cannibalised.
The external findings slight growth of coat at back (pup 2 and 6 from dam 59 of LD group) crushed pup (pup 13 from dam 64 of MD group) and small- thin pups (pup 10 and 13 from dam 66) at death were considered to be spontaneous and not related to test item treatment. - Histopathological findings:
- no effects observed
- Other effects:
- not examined
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental
- Generation:
- F1
- Effect level:
- 60 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: no treatment-related effects observed up to the highest dose tested
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Table 1:Mortality and clinical signs
Observation |
Dose Group |
|||
Control |
LDT |
MDT |
HDT |
|
[P]Generation - Males |
||||
Mortality |
0/10 |
0/10 |
0/10 |
2/10 |
|
|
|
found dead: no. 32 (MD 3) euthanasia: no. 35 (PMD 8) |
|
abnormal breathing (moderate) |
- |
- |
- |
2/10 |
abnormal breathing (severe) |
- |
- |
- |
1/10 |
diarrhoea |
10/10 |
10/10 |
10/10 |
9/10 |
moving the bedding |
- |
- |
10/10 |
10/10 |
nasal discharge (red) |
- |
2/10 |
3/10 |
1/10 |
piloerection (slight) |
- |
- |
- |
1/10 |
spontaneous activity reduced (moderate) |
- |
- |
- |
1/10 |
|
|
|
|
|
[P]Generation - Females |
||||
Mortality |
1/10 |
1/10 |
1/10 |
0/10 |
|
found dead: no. 44 (PMD 13) |
euthanasia: no. 58 (PND 0) |
found dead: no. 69 (GD 2) |
|
abnormal breathing |
1/10 |
1/10 |
1/10 |
4/10 |
alopecia (back) |
- |
1/10 |
- |
- |
alopecia (both forepaws) |
1/10 |
- |
- |
2/10 |
alopecia (shoulders) |
- |
- |
1/10 |
- |
alopecia (throat bilateral) |
- |
- |
3/10 |
- |
alopecia (throat left) |
- |
- |
1/10 |
- |
diarrhoea |
10/10 |
10/10 |
10/10 |
10/10 |
moving the bedding |
- |
3/10 |
9/10 |
10/10 |
nasal discharge (red) |
1/10 |
- |
- |
1/10 |
pale skin |
- |
1/10 |
- |
- |
piloerection (slight) |
- |
2/10 |
1/10 |
2/10 |
piloerection (moderate) |
- |
- |
1/10 |
1/10 |
salivation (slight) |
1/10 |
- |
1/10 |
3/10 |
salivation (moderate) |
1/10 |
1/10 |
- |
4/10 |
salivation (severe) |
- |
- |
- |
2/10 |
spontaneous activity reduced (moderate) |
- |
1/10 |
- |
- |
vocalisation |
- |
- |
- |
1/10 |
wasp waist (moderate) |
- |
1/10 |
- |
- |
Animals affected / total number of animals; Given in brackets: study day of death PMD = pre mating day; PND = post-natal day; GD = gestation day, MD- mating and post mating day
a Data extracted from pages (38) of the study report
Table 3: Pre- and Post-Natal Data - Summary
Group |
|
Corpora Lutea (CL) |
Implantation Sites (IS) |
Live Pups on PND 0 |
Live Pups on PND 4 (before) |
Live Pups on PND 4 (after) |
Live Pups on PND 13 |
Pre Implantation Loss (%) |
Post Implantation Loss (%) |
C |
Mean |
12.89 |
12.00 |
10.89 |
10.89 |
8.89 |
8.89 |
6.71 |
9.72 |
SD |
1.17 |
1.12 |
1.90 |
1.90 |
1.90 |
1.90 |
6.75 |
9.48 |
|
N |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
|
LD |
Mean |
12.25 |
12.25 |
9.44 |
10.13 |
8.13 |
8.13 |
0.00 |
15.20 |
SD |
2.12 |
2.12 |
3.64 |
2.70 |
2.70 |
2.70 |
0.00 |
15.48 |
|
N |
8 |
8 |
9 |
8 |
8 |
8 |
8 |
8 |
|
MD |
Mean |
13.25 |
12.75 |
11.88 |
11.75 |
9.88 |
9.75 |
3.59 |
6.74 |
SD |
1.91 |
1.75 |
1.81 |
1.67 |
1.81 |
1.67 |
5.16 |
7.38 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
|
HD |
Mean |
13.89 |
13.11 |
12.00 |
12.00 |
10.00 |
9.89 |
5.16 |
8.51 |
SD |
1.45 |
0.93 |
1.32 |
1.32 |
1.32 |
1.27 |
6.40 |
7.16 |
|
N |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
Table 4:Litter parameters for F1
Observation |
Dose Group (ppm) |
|||
Control |
LDT |
MDT |
HDT |
|
F1Generation |
||||
Mean Implantation Sites |
12.00 |
12.25 |
12.75 |
13.11 |
Number born live |
10.89 |
9.44 |
11.88 |
12.00 |
Pre Implantation loss [%] |
6.71 |
0.00 |
3.59 |
5.16 |
# Deaths Days 0-4 (%) |
0.00 |
2.81 |
0.89 |
0.00 |
# Deaths Days 4-13 (%) |
0.00 |
0.00 |
0.00 |
1.01 |
Mean litter size Day 0 |
10.89 |
10.38 |
11.88 |
12.00 |
Day 4 |
10.89 |
10.13 |
11.75 |
12.00 |
Day 13 |
8.89 |
8.13 |
9.75 |
9.89 |
|
|
|
|
aData extracted from pgs (56-58) of the study report.
Table 5: Mean Anogenital Distance and Nipple Retention
Group |
|
Male Pups |
Male Pup Weight (g) |
Cube Root of Pup Weight |
Anogenital Distance (mm) of Pups |
Relative Anogenital Distance of Pups |
Pup nipple retention (N) on PND 12 |
Female Pups |
Female Pup Weight (g) |
Cube Root of Pup Weight |
Anogenital Distance (mm) of Pups |
Relative Anogenital Distance Pups |
C |
Mean |
3.47 |
6.61 |
1.87 |
1.95 |
1.04 |
0.02 |
8.79 |
6.23 |
1.84 |
0.66 |
0.34 |
SD |
2.06 |
0.76 |
0.08 |
0.37 |
0.18 |
0.14 |
2.23 |
0.60 |
0.06 |
0.23 |
0.07 |
|
N |
51 |
51 |
51 |
51 |
51 |
51 |
47 |
47 |
47 |
49 |
47 |
|
LD |
Mean |
3.46 |
6.29 |
1.84 |
1.92 |
1.05 |
0.00 |
8.53 |
5.84 |
1.80 |
0.71 |
0.35 |
SD |
2.02 |
0.85 |
0.09 |
0.27 |
0.13 |
0.00 |
2.73 |
0.71 |
0.07 |
0.41 |
0.07 |
|
N |
46 |
45 |
45 |
49 |
45 |
44 |
40 |
40 |
40 |
48 |
40 |
|
MD |
Mean |
4.54 |
6.15** |
1.83** |
2.04 |
1.12* |
0.04 |
9.53 |
6.06 |
1.82 |
0.65 |
0.35 |
SD |
2.85 |
0.76 |
0.07 |
0.32 |
0.16 |
0.19 |
2.48 |
0.86 |
0.09 |
0.15 |
0.08 |
|
N |
56 |
57 |
57 |
57 |
57 |
56 |
38 |
38 |
38 |
39 |
38 |
|
HD |
Mean |
3.81 |
6.31 |
1.84 |
1.97 |
1.07 |
0.29 |
9.20 |
5.99 |
1.81 |
0.64 |
0.35 |
SD |
2.21 |
0.82 |
0.08 |
0.28 |
0.13 |
0.83 |
2.40 |
0.76 |
0.08 |
0.12 |
0.07 |
|
N |
52 |
52 |
52 |
53 |
52 |
51 |
56 |
56 |
56 |
56 |
56 |
Asterisks indicate statistically significant differences to control group C, with * p<0.05, ** p<0.01 and *** p<0.001
Applicant's summary and conclusion
- Conclusions:
- On the basis of this reproduction/developmental toxicity screening test with 2,4-Bismaleimidotoluene in male and female Wistar rats with dose levels of 10, 30, and 60 mg/kg body weight day the following conclusion can be made: No adverse effects of 2,4-Bismaleimidotoluene were found on male, females and pups at dose levels of 60 mg/kg body weight.
The NOAEL of 2,4-Bismaleimidotoluene in this study for general and reproductive toxicity screening is considered to be 60 mg/kg body weight.
Based on these results, the following NOAELs were derived:
parental NOAEL: 60 mg/kg
fertility NOAEL, females: 60 mg/kg
developmental NOAEL: 60 mg/kg
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