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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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: 224-675-8 | CAS number: 4443-26-9
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP study according to internationally accepted guideline. No deviations from guideline protocol.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 992
- Report date:
- 1992
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: EC Directive 88/302/EEC B.31 Teratogenicity Test - Rodent and Non-Rodent
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 1,3-dihydro-1,3-dioxo-2H-isoindole-2-hexanoic acid
- EC Number:
- 224-675-8
- EC Name:
- 1,3-dihydro-1,3-dioxo-2H-isoindole-2-hexanoic acid
- Cas Number:
- 4443-26-9
- Molecular formula:
- C14H15NO4
- IUPAC Name:
- 6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanoic acid
- Details on test material:
- Name of test material (as cited in study report): PAC
Lot/Batch number: 5A7990
Description: White crystalline powder
Purity: 99.48% w/w
Stability: Analytical confirmation of the stability of the substance in the vehicle was performed by the Sponsor and communicated to the Study Laboratory: Stability of the test material in the vehicle resulted to be about 20 days.
Constituent 1
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Italia
- Age at study initiation: 16-17 weeks old
- Weight at study initiation: 2700-3200 g
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% methylcellulose 400 cps aqueous solution
- Details on exposure:
- Concentration in vehicle: 0, 12.5, 25, 75 mg/ml
Total volume applied: 4 ml/kg bw/day - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- Mating period: 14 days
- Duration of treatment / exposure:
- 12 days: pregnant dams were dosed by gavage during days 6-18 of gestation.
- Frequency of treatment:
- Dosing regime: 7 days/week
- Duration of test:
- Dams were sacrificed on day 29 of gestation, i.e. 10 days after last dosage
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0 mg/kg bw/d
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
50 mg/kg bw/d
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
100 mg/kg bw/d
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
300 mg/kg bw/d
Basis:
actual ingested
- No. of animals per sex per dose:
- Number of dams and doses
20 at 0 mg/kg
20 at 50 mg/kg
20 at 100 mg/kg
20 at 300 mg/kg - Control animals:
- yes, concurrent vehicle
- Details on study design:
- The doses were selected on the ground of a preliminary teratogenicity study, performed using pregnant rabbits dosed orally (on days 6 – 18 of gestation) with PAC at 0, 100, 500 or 1000 mg/kg/day. Test design was based on OECD guideline 414. A number of treatment-related deaths were seen: at 1000 mg/kg/day, 4/6 decedents showed gastro-intestinal tract ulceration and at 500 mg/kg day 2/4 decedents showed oedema of the gastric submucosa. Surviving animals of these test groups showed reduced bodyweight gain. These maternally toxic treatments were associated with embryotoxicity (increased resorptions), reduced foetal weights and some skeletal anomalies (most retarded ossification of head or sternum). However no treatment-related malformed foetuses were seen. At 100 mg/kg/day, only slight reduction of bodyweight gain in treated does was seen.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION: Yes
WATER CONSUMPTION: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: not specified - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - Litter examinations: litter size, number of dead foetuses, foetal weight, sex ratio.
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Five animals (one from the control group (day 17), one from the low dose group (day 19), two from the mid-dose group (day 12 and day 24 and one from the high-dose group (day 12)) died during the study. All deaths were considered as incidental, although it could be possible that treatment induced a worsening of effects.
No clinical signs or behavioural changes were found in any experimental group. A dose-related decrease in maternal absolute body weight was recorded for all the treatment groups during PAC administration, achieving statistical significance at 300 mg/kg/day. Decreased body weight gain achieved statistical significance at 100 and 300 mg/kg/day during the treatment period. A slight recovery in body weight gain was observed at the end of exposure (day 19-29 of gestation) in the 300 mg/kg/day group. Changes in body weight were consistent with the decreased food intake recorded for all treatment groups during the administration period. A similar trend was observed also for water intake.
No pathological changes were found during the autopsy and no abortions were found in any group.
2 animals with only resorptions were present, one in the low-dose group and another in the mid-dose group.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Effects on fetus - litter examinations:
- An increase in the incidence of does with early resorptions was observed in all treated groups (30-35%) compared to controls (8.33%). This included two does, one in the low-dose group and another in high-dose group with only resorptions present. In addition, a statistically significant (p < 0.01) increase in the percentage of early resorptions (group total number of early resorptions/group total number of implantations) was observed in the mid- and high dose groups (12% and 11%, respectively), even with the exclusion of the 2 cases of only resorptions from the mean calculations.
- The mean viable foetal weight of the pups from the hig-dose group was significantly lower (16%, p < 0.01) than the respective controls. No other effects were observed in litter parameters. No treatment-related malformations, anomalies and variants were observed at any tested dose.
Effects on fetus - Gross:
- No treatment-related effects in any groups.
Effects on fetus - Soft tissue:
- No visceral malformations were found at any dosages.
Effects on fetus - Skeletal:
- No important differences were found between the skeletal anomalies and variants of the treated groups and dose of the control group.
- The head's examination did not show any malformation, anomaly or variant in any group.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Basis for effect level:
- other: embryotoxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Maternal effects
Parameter |
control
|
low dose |
medium dose |
high dose |
dose-response |
Number of dams examined |
20 |
20 |
20 |
20 |
|
Clinical findings during application of test substance |
- |
- |
- |
- |
- |
Mortality of dams state % |
5% |
5% |
10% |
5% |
- |
Abortions |
- |
- |
- |
- |
- |
Body weight gain (g) - day 0-6 |
27.5 |
52.3 |
22.5 |
20.7 |
|
day 6-19 |
318.3 |
154.6* |
94.2** |
-93.6** |
+ |
day 19-29 |
151.7 |
171.5 |
196.7 |
342.9** |
+ |
day 0-29 |
497.5 |
378.5 |
313.3 |
270.0 |
+ |
Pregnancies |
12/20 |
14/20 |
13/20 |
14/20 |
- |
Necropsy findings in dams dead before end of test |
Not examined |
Acute pneumonia |
Kidney - tubular dilatation atrophy
Liver - centrilobular necrosis and degeneration |
Kidney - tubular dilatation atrophy |
|
* p< 0.05; ** p< 0.01
Litter response
Parameter |
Mean# |
control |
low dose |
medium dose |
high dose |
dose-response |
Corpora lutea
|
A |
115/12 |
140/14 |
132/13 |
150/14 |
- |
B |
115/12 |
130/13 |
121/12 |
150/14 |
- |
|
Implantations
|
A |
105/115 91.30% |
128/140 91.43% |
102/132* 77.27% |
139/150 92.67% |
- |
B |
105/115 91.30% |
118/140 90.77% |
95/132** 78.51% |
139/150 92.67% |
- |
|
Early resorptions
|
A |
2/105 1.90% |
18/128*** 14.06% |
18/102*** 17.65% |
15/139** 10.79% |
- |
B |
2/105 1.90% |
8/118 6.78% |
11/95** 11.58% |
15/139** 10.79% |
- |
|
Early + late resorptions
|
A |
4/105 3.80% |
23/128*** 17.97% |
18/102** 17.65% |
20/139** 14.39% |
- |
B |
4/105 3.80% |
13/128* 11.02% |
11/95* 11.58% |
20/139** 14.39% |
|
|
total number of fetuses |
A |
105 |
128 |
102 |
139 |
- |
B |
105 |
118 |
92 |
139 |
- |
|
pre-implantation loss, %
|
A |
9.3 |
7.9 |
22.7* |
7.21 |
- |
B |
9.3 |
8.5 |
21.6* |
7.21 |
- |
|
post-implantation loss, % |
A |
5.0 |
17.5 |
20.2 |
13.9 |
- |
B |
5.0 |
11.1 |
13.5 |
13.9 |
- |
|
total number of litters |
A |
12 |
14 |
13 |
14 |
- |
B |
12 |
13 |
12 |
14 |
- |
|
live fetuses / litter |
A |
8.42 |
7.50 |
6.31 |
8.43 |
- |
B |
8.42 |
8.08 |
6.83 |
8.43 |
|
|
dead fetuses / litter |
A |
0.00 |
0.00 |
0.15 |
0.07 |
|
B |
0.00 |
0.00 |
0.17 |
0.07 |
- |
|
fetus weight (mean), g |
B |
47.64 |
45.62 |
48.03 |
40.53** |
- |
placenta weight (mean), g |
B |
7.17 |
7.44 |
7.85 |
7.09 |
- |
Fetal sex ratio, m/f
|
|
0.83 |
0.91 |
0.86 |
0.90 |
- |
*p< 0.05; ** p< 0.01; *** p< 0.001
#Mean A: all dams were included in the mean Mean B: the 2 cases of only resorptions were excluded
|
Examination of the fetuses
Parameter |
control
|
low dose |
medium dose |
high dose |
dose-response |
External malformations* [%] |
0.00 |
0.00 |
0.00 |
0.85 |
- |
External anomalies* [%] |
0.00 |
0.00 |
0.00 |
0.00 |
- |
Skeletal malformations* [%] |
0.00 |
0.00 |
0.00 |
0.00 |
- |
Skeletal anomalies* [%] |
15.84 |
21.90 |
18.29 |
10.17 |
- |
Skeletal variants* [%] |
29.70 |
41.90* |
37.80 |
22.03 |
- |
Visceral malformations* [%] |
0.00 |
0.00 |
0.00 |
0.00 |
- |
Visceral anomalies* [%] |
0.00 |
0.00 |
0.00 |
0.00 |
- |
Visceral variants* [%] |
0.00 |
0.00 |
0.00 |
0.00 |
- |
* p< 0.05
|
Applicant's summary and conclusion
- Conclusions:
- LO(A)EL maternal toxic effects 100 mg/kg bw/day. General toxicity, decreased body weight and body weight gain.
NO(A)EL maternal toxic effects 50 mg/kg bw/day
LO(A)EL embryotoxic / teratogenic effects 300 mg/kg bw/day. Statistically significant decrease in the mean viable foetal weight of the pups.
NO(A)EL embryotoxic / teratogenic effects 100 mg/kg bw/day - Executive summary:
20 pregnant female New Zealand white rabbits/group were exposed to 0, 50, 100 and 300 mg/kg/day by gavage. Pregnant dams were dosed by gavage during days 6-18 of gestation. On day 29 of gestation, animals were sacrificed and the potential effects of the treatment on pregnancy and foetuses were analysed.
Maternal toxicity (decreased body weight and body weight gain) was observed at ≥ 100 mg/kg bw/day.
An increased incidence of early resorptions was observed in all the treatment groups and 2 dams with only resorptions were observed, one in the 50 mg/kg/day and another in the 100 mg/kg/day groups. However,the incidences of these findings were in the range of normal variability seen in this strain. The group mean number of early resorptions in the 100 and 300 mg/kg/day groups was also in the range of normal variability and the increase in the percentage of early resorption observed in these treatment groups was considered to be due to a high individual value.
A statistically significant decrease in the mean viable foetal weight of the pups was observed at 300 mg/kg/day. No treatment-related malformations, anomalies and variants were observed at any tested dose.
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.