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EC number: 203-271-5 | CAS number: 105-11-3
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- repeated dose toxicity: oral, other
- Remarks:
- 7-week DRF repeat-dose toxicity study ; conducted as a range-finder prior to a chronic Carcinogencity study
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 451 (Carcinogenicity Studies)
- Deviations:
- not specified
- GLP compliance:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Details on species / strain selection:
- Common rodent species historically used in carcinogenicity assays; note that mice of strain: B6C3F1 (male/female) were additionally dosed in parallel
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: two animal species, Fischer 344 rats and B6C3F1 mice, used – sourced from Recognised Supplier.
- Females (if applicable) nulliparous and non-pregnant: Yes.
- Age at study initiation: ca. 6 weeks old (rats) ; ca. 6 weeks old mice.
- Weight at study initiation:
- Fasting period before study:
- Housing: Group housing four or five by sex, polycarbonate cages and stainless steel mesh. Filter paper was changed every 2 weeks. Clean cages and bedding with hardwood chip bedding renewed twice weekly.
- Diet (e.g. ad libitum): ad libitum, (test item treated/untreated, as applicable) Lab-Blox basal diet
- Water (e.g. ad libitum): ad libitum. Acidulated water..
- Acclimation period: 2 weeks
DETAILS OF FOOD AND WATER QUALITY: Information provided in the full study report.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 26 °C
- Humidity (%): 45 - 55
- Air changes (per hr): Filtered, 12 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 16 hours dark / 8 hours light - Route of administration:
- oral: feed
- Vehicle:
- not specified
- Details on exposure:
- - DIET PREPARATION
- Rate of preparation of diet (frequency):
The mixture was prepared once weekly.
- Mixing appropriate amounts with (Type of food):
The basal laboratory diet for both dosed and control animals consisted of Wayne Lab-Blox meal. Test item was administered to the dosed animals as a component of the diet. The test item was removed from its container and a proper amount was blended with an aliquot of the feed using a mortar and pestle. Once visual homogeneity was attained, the mixture was placed in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in double plastic bags and stored in the dark at 4°C. The mixture was prepared once weekly.
- Storage temperature of food:
stored in the dark at 4°C
- Other: Dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed.
- Duration of treatment / exposure:
- 2 years (or 104 weeks) treatment and 1 week observation
- Frequency of treatment:
- daily
- Post exposure period:
- 1 week
- No. of animals per sex per dose:
- 20 per control
50 per low dose (rat: 375 ppm and mouse: 750 ppm)
50 per high dose (rat: 750 ppm and mouse: 1500 ppm) - Control animals:
- yes, plain diet
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- Statistical analysis was perfomed not limited to:
1. Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier (1958) and are presented in the report.
2. Animals were statistically censored as of the time that they died of other than natural causes or were found to be missing; animals dying from natural causes were not statistically censored. Statistical analyses for a possible dose-related effect
on survival used the method of Cox (1972) when testing two groups for equality and used Tarone's (1975) extensions of Cox's methods when testing a dose-related trend. One-tailed P-values have been reported for all tests except the departure from linearity test, which is only reported when its two-tailed P-value is less than 0.05.
3. The incidence of neoplastic or nonneoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site (numerator) to the number of animals in which that site was examined (denominator). Additional considerations were given.
4. one-tailed Fisher exact test (Cox, 1970, pp. 48-52) was used to compare the tumor incidence of a control group to that of a group of treated animals at each dose level.
5. Bonferroni inequality (Miller, 1966, pp. 6-10) requires that the P-value for any comparison be less than or equal to 0.05/k.
6. The Cochran-Armitage test for linear trend in proportions, with continuity correction (Armitage, 1971, pp. 362-365), was also used when appropriate.
7. time-adjusted analysis was applied when numerous early deaths resulted from causes that were not associated with the formation of tumors.
8. life-table methods were used to analyze the incidence of tumors. Curves of the proportions surviving without an observed tumor were computed as in Saffiotti et al. (1972).
9. The approximate 95 percent confidence interval for the relative risk of each dosed group compared to its control was calculated from the exact interval on the odds ratio (Gart, 1971). - Clinical signs:
- no effects observed
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- The Tarone test for association between dosage and mortality was not significant for either males or females.
Females: 78 percent (39/50) of the high dose, 78 percent (38/49) of the low dose, and 90 percent (18/20)
Males: 70 percent (35/50) of the high dose, 78 percent (39/50) of the low dose, and 85 percent (17/20) of the controls survived on test until the termination of the study. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose-related mean body weight depression was apparent in both male and female rats at the dose levels tested.
- Food consumption and compound intake (if feeding study):
- not examined
- 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:
- 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
- Neuropathological findings:
- not examined
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Microscopic examination revealed a variety pf neoplasms in male and female rats with the highest incidence in the urinary, endocrine and reproductive systems. Except for the urinary system the distribution of neoplasms was judged to be random among dosed and control animals, and the neoplasms observed were of the type commonly observed in aging Fischer 344 rats.
Treatment related effects observed appeared confined to females in the urinary tract. - Other effects:
- no effects observed
- Relevance of carcinogenic effects / potential:
- Within female and male rats:
1. transitional-cell papilloma 0/45, 2/46, 1/43, and 4/44 in the low dose males, high dose males, low dose females, and high dose females, respectively;
2. transitional-cell carcinoma 0/45, 0/46, 1/43, and 7/44 in the low dose males, high dose males, low dose females, and high dose females, respectively;
3. squamous-cell carcinomas 0/45, 0/46,-1/43, and 0/44 in the low dose males, high dose males, low dose females, and high dose females, respectively
Cochran-Armitage test for the female rats indicated a significant positive association between the concentrations administered and the incidences of these tumors when combined. The high dose to control Fisher exact comparison for females was also significant.
In female mice there was a significant positive association between chemical administration and the incidence of hepatocellular neoplasms. However, the Fisher exact comparisons did not achieve statistical significance. The authors concluded that this was not conclusive to relate to a test item effect given the historical range for the B6C3F1 mouse. - Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 375 ppm
- System:
- urinary
- Organ:
- bladder
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Under the conditions of this study, there was a positive dose-related association between test item administration and neoplastic effects females in the urinary tract.
- Executive summary:
The study was performed as a 104 week chronic carcinogenicity study using methods equivalent or similar to the requirements of OECD Guideline 453, to evaluate the potential carcinogenicity of the test item via the dietary route. Chronic toxicity tests were- conducted with both Fisher 344 rats and B6C3F1 mice. F344 male/female rats were distributed among two treatment groups of low: 375 ppm and high: 750 ppm, each consisting of fifty males and fifty females. B6C3F1 strain male/female mice were distributed among two treatment groups of low: 750 ppm and high: 1500 ppm, each consisting of fifty males and fifty females. Negative controls consisted of twenty rats, and/or mice untreated with plain diet. The test item was administered for 102-weeks through basal laboratory diet supplied ad libitum. Observation continued for one week post administration. Rats and mice were necropsied post termination. The basal laboratory diet for both dosed and control animals consisted of Wayne Lab-Blox meal. Test item was administered to the dosed animals as a component of the diet. The test item was removed from its container and a proper amount was blended with an aliquot of the feed using a mortar and pestle. Once visual homogeneity was attained, the mixture was placed in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in double plastic bags and stored in the dark at 4°C. The mixture was prepared once weekly. The report indicated that dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed.
There were no significant positive associations between the concentrations of test item administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Distinct dose-related mean body weight depression was observed among rats and slight mean body weight depression, relative to controls, was observed among mice, indicating that the dosages of test item administered may have approximated the maximum tolerated concentrations. Tumors of the urinary bladder were observed only in dosed rats. For female rats, there was a significant positive association between concentration administered and the incidences of a combination of urinary bladder neoplasms. The high dose to control Fisher exact comparison was also significant for these tumors in female rats. No other test item related neoplasms were observed in male rats or mice of either sex or were considered as relevant. In female mice there was a significant positive association between chemical administration and the incidence of hepatocellular neoplasms. However, the Fisher exact comparisons did not achieve statistical significance. The authors concluded that this was not conclusive to relate to a test item effect given the historical range for the B6C3F1 mouse.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 979
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- Sub-chronic range finding assay conducted in rats and mice:
Documented method was conducted in the rat and mouse via diet for 7-weeks (49 days) treatment with 1 week observation period and one rat and two mouse negative control groups (untreated) - Deviations:
- yes
- Remarks:
- See "version / remarks"
- Principles of method if other than guideline:
- - Principle of test:
Sub-chronic range finding assay conducted in rats and mice: Documented method was conducted in the rat and mouse via diet for 7-weeks (49 days) treatment with 1 week observation period and one rat and two mouse negative control groups (untreated)
- Short description of test conditions: To establish the concentrations of the test item for administration to dosed animals in the chronic/carcinogenicity studies, Subchronic toxicity tests were- conducted with both rats and mice. Rats were distributed among ten groups, each consisting of five males and five females. Mice were distributed among ten groups, each consisting of five males and five females. The test item was administered for 7-weeks through basal laboratory diet supplied ad libitum at doses up to 10,000 ppm in rats and 14,700 ppm in mice. With one rat negative control and one mice negative control. Observation continued for one week post administration.
- Parameters analysed / observed: Mortality, clinical signs, bodyweights, necropsy - GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- p-benzoquinone dioxime
- EC Number:
- 203-271-5
- EC Name:
- p-benzoquinone dioxime
- Cas Number:
- 105-11-3
- Molecular formula:
- C6H6N2O2
- IUPAC Name:
- N-[(1Z,4Z)-4-(hydroxyimino)cyclohexa-2,5-dien-1-ylidene]hydroxylamine
- Test material form:
- solid
- Details on test material:
- Name of test material (as cited in study report): p-quinone dioxime
- Other names: 1,4-benzoquinone dioxime ; p-benzoquinone dioxime
- Analytical purity: > 85 to 95%wt (sum of two isomers) – based on the analysis within the report.
- Lot/batch No.: Not reported, sourced from Pfaltz and Bauer Chemical Company
- Expiration date of the lot/batch: Not reported.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Details on species / strain selection:
- Common rodent species historically used in carcinogenicity assays; note that mice of strain: B6C3F1 (male/female) were additionally dosed in parallel
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: two animal species, Fischer 344 rats and B6C3F1 mice, used – sourced from Recognised Supplier.
- Females (if applicable) nulliparous and non-pregnant: Yes.
- Age at study initiation: ca. 4 weeks old (rats) ; ca. 4 weeks old mice.
- Weight at study initiation:
- Fasting period before study:
- Housing: Group housing four or five by sex, polycarbonate cages and stainless steel mesh. Filter paper was changed every 2 weeks. Clean cages and bedding with hardwood chip bedding renewed twice weekly.
- Diet (e.g. ad libitum): ad libitum, (test item treated/untreated, as applicable) Lab-Blox basal diet
- Water (e.g. ad libitum): ad libitum. Acidulated water..
- Acclimation period: 2 weeks
DETAILS OF FOOD AND WATER QUALITY: Information provided in the full study report.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 26 °C
- Humidity (%): 45 - 55
- Air changes (per hr): Filtered, 12 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 16 hours dark / 8 hours light
Administration / exposure
- Route of administration:
- oral: feed
- Details on route of administration:
- test item was incorporated into the basal laboratory diet and supplied ad libitum
- Vehicle:
- not specified
- Details on oral exposure:
- - DIET PREPARATION
- Rate of preparation of diet (frequency): The mixture was prepared once weekly.
- Mixing appropriate amounts with (Type of food): The basal laboratory diet for both dosed and control animals consisted of Wayne Lab-Blox meal. Test item was administered to the dosed animals as a component of the diet. The test item was removed from its container and a proper amount was blended with an aliquot of the feed using a mortar and pestle. Once visual homogeneity was attained, the mixture was placed in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in double plastic bags and stored in the dark at 4°C. The mixture was prepared once weekly.
- Storage temperature of food: stored in the dark at 4°C
- Other: Dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed.
- Duration of treatment / exposure:
- 7 weeks (49 days)
- Frequency of treatment:
- Daily feed
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm
- Remarks:
- Rat untreated - (control)
- Dose / conc.:
- 680 ppm
- Remarks:
- Rat group 1 - treated
- Dose / conc.:
- 1 000 ppm
- Remarks:
- Rat group 2 - treated
- Dose / conc.:
- 1 470 ppm
- Remarks:
- Rat group 3 - treated
- Dose / conc.:
- 2 160 ppm
- Remarks:
- Rat group 4 - treated
- Dose / conc.:
- 3 150 ppm
- Remarks:
- Rat group 5 - treated
- Dose / conc.:
- 4 600 ppm
- Remarks:
- Rat group 6 - treated
- Dose / conc.:
- 6 800 ppm
- Remarks:
- Rat group 7 - treated
- Dose / conc.:
- 10 000 ppm
- Remarks:
- Rat group 8 - treated
- Dose / conc.:
- 0 ppm
- Remarks:
- Mouse untreated - (control)
- Dose / conc.:
- 680 ppm
- Remarks:
- Mouse group 1 - treated
- Dose / conc.:
- 1 000 ppm
- Remarks:
- Mouse group 2 - treated
- Dose / conc.:
- 1 470 ppm
- Remarks:
- Mouse group 3 - treated
- Dose / conc.:
- 3 150 ppm
- Remarks:
- Mouse group 4 - treated
- Dose / conc.:
- 4 600 ppm
- Remarks:
- Mouse group 5 - treated
- Dose / conc.:
- 6 800 ppm
- Remarks:
- Mouse group 6 - treated
- Dose / conc.:
- 10 000 ppm
- Remarks:
- Mouse group 7 - treated
- Dose / conc.:
- 14 700 ppm
- Remarks:
- Mouse group 8 - treated
- No. of animals per sex per dose:
- 5 males / 5 females
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Study was a DRF for a chronic carcinogenicity study.
- Rationale for animal assignment (if not random): Random.
- Rationale for selecting satellite groups: Not applicable.
- Post-exposure recovery period in satellite groups: Not applicable.
- Section schedule rationale (if not random): Not applicable.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Rats: 4600 ppm only, convulsions were reported in this female group only. No effects were reported in males at 4600 ppm or in higher 6800 ppm or 10000 ppm dose level.
No other clinical abnormalities which could be attributed, to administration of the compound were observed.
See table 1.0 and table 2.0 in 'any other information on results incl. tables' - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 10000 ppm: Females 5/5 mortality ; Males 4/5 mortality
6800 ppm: Females 4/5 mortality ; Males 3/5 mortality
4600 ppm: Femles - no mortality ; Males - no mortality
No mortalities were observed in rats at les than 6800 ppm
Mice: no mortality less than 10000ppm (2/5 females only).
See table 1.0 and table 2.0 in 'any other information on results incl. tables' - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean bodweight gain, decreases relative to controls were observed at all dose levels.
See table 1.0 and table 2.0 in 'any other information on results incl. tables' - Food consumption and compound intake (if feeding study):
- not examined
- 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:
- 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):
- No macroscopic effects post-necropsy were reported in the study report. (Necropsy was conducted)
- Neuropathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Rats: 4600 ppm only, convulsions were reported in this female group only. No effects were reported in males at 4600 ppm or in higher 6800 ppm or 10000 ppm dose level.
See table 1.0 and table 2.0 in 'any other information on results incl. tables' - Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
Effect levels
- Dose descriptor:
- LOAEL
- Effect level:
- >= 680 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: LOAEL in rats and mice (male/female)
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Table 1.0 – Rat, 7 week DRF results:
Dose / ppm |
Weight gain % * |
Survival ** |
Convulsions ** |
|||
|
Females |
Male |
Females |
Males |
Females |
Males |
10000 |
-- |
-137 |
0/5 |
1/5 |
0/5 |
0/5 |
6800 |
-66 |
-114 |
1/5 |
3/5 |
0/5 |
0/5 |
4600 |
-43 |
-99 |
5/5 |
5/5 |
5/5 ** |
0/5 |
3150 |
-27 |
-59 |
5/5 |
5/5 |
0/5 |
0/5 |
2160 |
-18 |
-19 |
5/5 |
5/5 |
0/5 |
0/5 |
1470 |
-17 |
-6 |
5/5 |
5/5 |
0/5 |
0/5 |
1000 |
-13 |
-18 |
5/5 |
5/5 |
0/5 |
0/5 |
680 |
-2 |
-26 |
5/5 |
5/5 |
0/5 |
0/5 |
0 (control) |
N/A |
N/A |
5/5 |
5/5 |
0/5 |
0/5 |
|
|
|
|
|
|
|
Where:
* indicative of mean body weight gain less than that of controls.
** number of observed/number originally in group.
Table 2.0 – Mice, 7 week DRF results:
Dose / ppm |
Weight gain % * |
Survival ** |
||
|
Females |
Male |
Females |
Males |
14700 |
-- |
-34 |
0/5 |
|
10000 |
-12 |
-22 |
3/5 |
5/5 |
6800 |
-5 |
-5 |
5/5 |
5/5 |
4600 |
-7 |
-9 |
5/5 |
5/5 |
3150 |
-4 |
+1 |
5/5 |
5/5 |
1470 |
-12 |
-9 |
5/5 |
5/5 |
1000 |
-6 |
+2 |
5/5 |
5/5 |
680 |
-1 |
-4 |
5/5 |
5/5 |
0 (control) |
N/A |
N/A |
5/5 |
5/5 |
|
|
|
|
|
Where:
* indicative of mean body weight gain less than that of controls.
** number of observed/number originally in group.
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, the lowest-observed-adverse-effect level (LOAEL) for males and females is considered to be 680 ppm following 7 weeks test item administration.
- Executive summary:
The study was performed as a 7 week dietary range finding sub-chronic study using methods equivalent or similar to the requirements of OECD Guideline 407, to evaluate the potential toxicity of the test item prior to a definitive 2 year carcinogenicity study. Sub-chronic toxicity tests were- conducted with both rats and mice. Fisher 344 male/female rats were distributed among ten groups, each consisting of five males and five females. B6C3F1 strain male/female mice were distributed among ten groups, each consisting of five males and five females. The test item was administered for 7-weeks through basal laboratory diet supplied ad libitum at doses up to 10,000 ppm in rats and 14,700 ppm in mice. With respective negative controls. Observation continued for one week post administration. Rats and mice were necropsied post termination. The basal laboratory diet for both dosed and control animals consisted of Wayne Lab-Blox meal. Test item was administered to the dosed animals as a component of the diet. The test item was removed from its container and a proper amount was blended with an aliquot of the feed using a mortar and pestle. Once visual homogeneity was attained, the mixture was placed in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in double plastic bags and stored in the dark at 4°C. The mixture was prepared once weekly. The report indicated that dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed. Under the conditions of the study, the lowest-observed-adverse-effect level (LOAEL) for males and females is considered to be 680 ppm following 7 weeks test item administration.
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