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EC number: 447-010-5 | CAS number: 670241-72-2 ISONONYLBENZOAT
- 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
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 23. May 2003 - 05. Aug. 2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 004
- Report date:
- 2004
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Benzoic acid isononylester
- Cas Number:
- 670241-72-2
- IUPAC Name:
- Benzoic acid isononylester
- Details on test material:
- test item : Benzoic acid isononylester
ID no. : 0649/82188
Batch no. : 1276/00576
Appearance : colourless, clear liquid
Storage conditions : room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Italy s.r.l., San Pietro al Natisone (UD), Italy
- Age at study initiation: 6 - 7 weeks
- Weight at study initiation: (P) Males: 185.9 - 201.0 g; Females: 160.8 - 182.3 g
- Fasting period before study: no
- Housing: The animals were housed in a limited access rodent facility. During the pre-mating period, animals were housed up to 5 of one sex to a cage, in clear polycarbonate cages measuring 59x38.5x20 cm with a stainless steel mesh lid and floor (Techniplast Gazzada S.a.r.l., Buguggiate, Varese). Each cage tray held absorbent paper which was inspected and changed at least 3 times a week. During the mating period, animals were housed on the basis of one male to one female in clear polycarbonate cages measuring 42x26x18cm with a stainless steel mesh lid and floor (Techniplast Gazzada S.a.r.l., Buguggiate, Varese). Each cage tray held absorbent material which was inspected and changed daily. The males were re-caged after mating as they were be fore mating. After mating, the females were transferred to individual clear polycarbonate solid bottomed cages measuring 42x26x18cm (Techniplast Gazzada S.a.r.l., Buguggiate, Varese). Suitable nesting material was provided and was changed at least 3 times a week.
- Diet: A commercially available laboratory rodent diet (Altromin MT pelleted diet, D-32770 Lage, Postfach 1120, Germany) was offered ad libitum throughout the study.
- Water: ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 2°C
- Humidity (%): 55% ± 15%
- Air changes (per hr): 15 to 20
- Photoperiod (hrs dark / hrs light): 12 hrs / 12 hrs
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: prepared daily in polyethylene glycol (PEG 400)
VEHICLE
- Justification for use and choice of vehicle (if other than water): standard vehicle in toxicology studies
- Concentration in vehicle: 10, 30, 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight - Details on mating procedure:
- Mating was monogamous (one male to one female). A vaginal smear was taken from the day after the start of mating until sperm identification and/or copulation plugs were found. The pairing combinations of any animals which have not had positive identification of mating after 14 days of pairing will be changed within each treatment group. The subsequent pairing will be monitored for mating as described above for a maximum period of 14 days. If no mating oceurs the females will be killed at least 7days after the last day of the mating session.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prior to commencement of treatment, analysis was performed to confirm that the proposed formulation procedure was acceptable and that the stability of the formulation was satisfactory . Sampies of the formulations prepared during the first and the last week of treatment were analysed to check the concentration and the homogeneity.
- Duration of treatment / exposure:
- Males: Animals were dosed once a day, 7 days a week, for a minimum of 4 consecutive weeks prior to pairing and thereafter through the day be fore necropsy. Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
Females: Animals were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing and thereafter during gestation and post-partum periods, until the day before necropsy (Day 4 post-partum). During the gestation period, dose volumes were calculated according to individual body weight on Days 0, 7, 14 and 20 post-coitum and on Day 1 post-partum. Thereafter individual dose volumes remained constant. - Frequency of treatment:
- once daily
- Details on study schedule:
- On the day of allocation, 7 days prior to the start of treatment, all animals were weighed. Animals at the extremes of the weight distribution were excluded to leave the required number of animals. The rats were allocated to the 4 groups by computerised stratified randomisation to give approximately equal initial group mean body weights. Males: Animals were dosed once a day, 7 days a week, for a minimum of 4 consecutive weeks prior to pairing and thereafter through the day be fore necropsy. Females: Animals were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing and thereafter during gestation and post-partum periods, until the day before necropsy (Day 4 post-partum).
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 100, 300, 1000 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 10
- Details on study design:
- - Dose selection rationale: Dose selection on basis of a confirmatory study (RTC 40330EXT)
- Rationale for animal assignment (if not random): random - Positive control:
- none
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day on working days, and once on weekends and public holidays. Examination of individual animals for signs of reaction to treatment was carried out daily, prior to dosing, 30 minutes, 1 and 2 hours after dosing.
- Full records were maintained for all measurements and observations.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once per treatment week, and whenever possible at 7 day intervals, each animal was observed and any clinical signs were recorded.
BODY WEIGHT: Yes
- Time schedule for examinations: Males: Animals were weighed on the day of allocation to treatment groups, on the day that treatment commenced, weekly thereafter and just prior to necropsy. Females: Animals were weighed on the day of allocation to treatment groups, weekly from the first day of treatment to mating, on Days 0, 7, 14 and 20 post-coitum and on Days 1 and 4 postpartum.
OTHER: - Oestrous cyclicity (parental animals):
- not examined
- Sperm parameters (parental animals):
- not examined
- Litter observations:
- As soon as possible after parturition (Day 0 or 1 post-partum), the total litter size (live and dead) was counted, live pups were individually identifIed within the litter, sexed and examined for external abnormalities. All litters were weighed on Day 1 post-partum. All litters were examined daily for dead and abnormal pups. The pups were also weighed on Day 4 post-partum. All pups found dead were necropsied.
- Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: The males were killed after the mating of females with carbon dioxide.
- Maternal animals:The females with live pups were killed on Day 4 post-partum with carbon dioxide. Females which had not given birth 25 days after the positive identification of mating were killed shortly after.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues of abnormalities, seminal veshicles. epididymides, testes, prostate gland, ovaries, uterus and vagina were preserved. Detailed histopathological examination was performed on ovaries, testes, and epididymides from the control and the high dose groups. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. Necropsy of pups also comprised the confirmation of sex by gonadal inspection.
HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
SACRIFICE
- All viable pups were euthanised by intrascapular injection of Tanax on Day 4 post-partum.
GROSS NECROPSY
All pups found dead in the cage were necropsied. All live pups were killed on Day 4 postpartum and examined for the following:
a) external and internal abnormalities;
b) sex confirmation by gonadal inspection. - Statistics:
- For continuous variables the significance of the differences amongst group means was assessed by Dunnett's test or a modified t test, depending on the homogeneity of data. The homogeneity of the data was assessed by Bartlett's test. Statistical analysis of non-continuous variables was carried out by means of the Kruskal-Wallis test and intergroup differences between the control and treated groups assessed by a non-parametric version of the Williams test. The mean values, standard deviations were calculated from actual values in the computer without rounding off. Statistical analysis of histopathological findings was carried out by means of the nonparametric Kolmogorov-Smirnov test.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- 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:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
Clinical signs and pre- and post-dose observations: Clinical signs observed at weekly intervals in FO males and females were limited to common
conditions of the skin and fur. Rales were occasionaIly observed at pre- and post-dose observations, in controls and in groups 2 and 4 male animals, and in groups 3 and 4 females (data not tabulated). Soft faeces were recorded during cages observation for control and treated groups.
Body weights: A statistical significant lower body weight was observed in male animals of group 2 compared to controls on study day 15 (dosing phase). This difference was not considered treatment related since no other differences in body weight and/or body weight gain were noted between the treated and control groups. Body weight and body weight gain for female animals were generaIly comparable between the treated and control groups before mating and during gestation and post-partum periods.
Food consumption: Food consumption was unaffected by the treatment.
Reproductive parameters: Irregular oestrus cycles were observed in treated groups and also in controls. However, a high incidence of animals with irregular oestrus cycles was noted in the treated groups compared to controls. This finding was not considered to be of toxicological significance
since no effects on relevant fertility parameters were observed. The copulatory and fertility index as weIl as the pre-coital intervals were not affected by the treatment.
Implantation, pre-birth loss data and gestation length: The gestation periods were similar between the groups. No significant differences were observed for the number of implantations, corpora lutea and pre-birth loss in treated groups compared to controls.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Basis for effect level:
- other: overall results; body weight, body weight gain, food consumption, fertility index, pre-coital interval, copulatory index, histopathology of ovaries and testes, litter development
- Remarks on result:
- other: Generation not specified (migrated information)
Results: F1 generation
General toxicity (F1)
- 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:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
Sex ratios: No statistically significant differences were observed in the sex ratios between the groups.
Pre-weaning clinical signs of Fl pups: Pre-weaning clinical signs did not show treatment-related effects.
Necropsy findings in decedent pups: Decedent pups were found in treated groups including controls. One female in group 2 was found dead on Day 0 post-partum and a total of 14 pups were humanely sacrificed. No abnormalities were noted at necropsy for these pups (data not presented). One female in group 4 had total litter loss. No relevant fmdings that could be treatment-related were reported.
Necropsy findings in Fl pups at Day 4 post-partum: No significant fmdings were observed between the groups at necropsy of the pups.
Absolute and relative organ weights in FO males: Statistically significant higher relative organ weights of epididymides and testes were observed in group 2 compared to controls. These differences were not considered to be of toxicological relevance since no dose-dependency was observed.
Macroscopic observations: No macroscopic observation was reported in the treated animals that could be considered to be treatment-related.
Microscopic observations: The histopathological examination of the ovaries, testes and epididymides did not reveal any evident differences between the findings observed in the treated and control animals that could be considered treatment-related. Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages. No abnonnalities were noted.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- > 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Litter data at birth and on Day 4 post-partum - Group mean data
|
|
At birth |
On Day 4 |
|||||||
Group |
|
Litter total |
Live litter size |
Pup loss % |
Litter wt (g) |
Mean pup wt (g) |
Live litter size |
Cumulative loss % |
Litter wt. (g) |
Mean pup wt. (g) |
1 |
(n) |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
|
Mean |
14.7 |
14.2 |
3.5 |
86.6 |
6.4 |
13.3 |
9.3 |
128.6 |
9.6 |
|
SD |
1.2 |
1.5 |
3.9 |
16.5 |
0.5 |
1.6 |
4.3 |
28.4 |
1.1 |
|
|
|
|
|
|
|
|
|
|
|
2 |
(n) |
9 |
9 |
9 |
8 |
8 |
8 |
8 |
8 |
8 |
|
Mean |
14.3 |
13.9 |
3.8 |
87.4 |
6.5 |
13.3 |
8.8 |
122.9 |
9.4 |
|
SD |
2.7 |
3.1 |
7.9 |
18.9 |
0.5 |
3.3 |
8.4 |
26.2 |
1.2 |
|
|
|
|
|
|
|
|
|
|
|
3 |
(n) |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
|
Mean |
14.0 |
13.4 |
4.0 |
82.3 |
6.4 |
13.0 |
6.3 |
120.0 |
9.5 |
|
SD |
3.9 |
3.7 |
7.0 |
17.5 |
0.8 |
3.6 |
9.3 |
23.6 |
1.4 |
|
|
|
|
|
|
|
|
|
|
|
4 |
(n) |
7 |
7 |
7 |
6 |
6 |
6 |
6 |
6 |
6 |
|
Mean |
14.6 |
11.3 |
22.2 |
69.6 |
5.9 |
11.7 |
19.1 |
100.6 |
8.8 |
|
SD |
1.8 |
5.7 |
35.6 |
12.4 |
0.6 |
2.7 |
12.0 |
12.8 |
1.2 |
|
|
|
|
|
|
|
|
|
|
|
* = Statistically significantly different from control group value at p < 0.05
Applicant's summary and conclusion
- Conclusions:
- On the basis of the results, the dosage of 1000 mg/kg/day could be considered as the NOAEL.
- Executive summary:
The effects on reproduction and development of the offspring were evaluated after oral administration of BENZOIC ACID ISONONYLESTER in male and female rats. The test item was given before and during mating and throughout the gestation period until Day 3 post-partum at dosages of 100, 300 and 1000 mglkg/day. Body weight, body weight gain and food consumption were not affected by treatment in male or female animals. Reproductive parameters such as fertility index, pre-coital interval and copulatory index did not show significant differences in treated groups compared to controls. A slight reduction in mean pup weight and consequently in litter weight was noted in group 4 females at birth and on Day 4 post-partum. The histopathological examination of the ovaries, testes (including the stage in the spermatogenic cycle) did not reveal any evident differences between the findings observed in the treated and control animals. On the basis of the results, the dosage of 1000 mg/kg/day could be considered as the NOAEL.
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