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EC number: 932-019-3 | CAS number: -
- 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:
- toxicity to reproduction
- Remarks:
- other: OECD 422
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- March 2010- October 2010
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: OECD Guideline 422 study conducted under GLP conditions at professional contract laboratory
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- KGA
- IUPAC Name:
- KGA
- Reference substance name:
- L-xylo-hex-2-ulosonic acid
- EC Number:
- 208-403-5
- EC Name:
- L-xylo-hex-2-ulosonic acid
- Cas Number:
- 526-98-7
- Molecular formula:
- C6H10O7
- IUPAC Name:
- L-sorbosonic acid
- Reference substance name:
- 342385-52-8
- Cas Number:
- 342385-52-8
- IUPAC Name:
- 342385-52-8
- Details on test material:
- KGA is 2 keto-L-gulonic acid anhydrous, which is a precursor to ascobic acid (vitamin C). KGA and Ascorbic Acid are the two primary constituents making up the multiconstituent substance KGA Greens. The remainder of KGA Greens are various other sugars and organic acids.
Constituent 1
Constituent 2
Constituent 3
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc., Indianapolis, IN
- Age at study initiation:
- Weight at study initiation: males: 244-296 g; females: 173-205 g
- Fasting period before study:
- Housing: Stainless steel, suspended, wire bottom cages for all animal during the pre-mating period. Plastic cages during mating and for females and pups after mating. Animals individually housed.
- Diet (e.g. ad libitum): PMI Feeds, Inc. Forumlab #5008, available ad libitum. Analyzed by manufacturer for nutrient content.
- Water (e.g. ad libitum): Municipal water supply analyzed by TNRCC Water Utilities Division; tap water, available ad libitum (automatic system)
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 =/- 3 degrees C
- Humidity (%): 30-70%
- Air changes (per hr): 10-12 air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle
IN-LIFE DATES: From: 19 April 2010 (beginning of definitive test) To: 11 June 2010
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- The test animals were dosed by oral gavage with an appropriately sized stainless stell ball-tipped dosing needle and syringe since gavage dosing assures the proper dose presentation. Three groups (Groups II, III and IV) of ten males and ten females each were dosed daily at 500 mg/kg, 1000 mg/kg and 2000 mg/kg, respectively. A concurrent vehicle control group (Group I, ten males and ten females) was dosed with the vehicle, deionized water. Groups were dosed daily at approximately the same time each day and dose amounts were adjusted weekly based on the latest body weight. All animals were dosed at a constant volume of 8.0 mL/kg. Males and females were dosed for 14 days prior to mating. Males were dosed for another 14 days during mating, for a total of 28 days. Females were dosed through mating and until one day prior to termination (lactation Day 4 for those that delivered and Study Day 53 for those that did not deliver).
- Details on mating procedure:
- - M/F ratio per cage: one female was cohabited with one male
- Length of cohabitation: two weeks or until signs of pregnancy were observed
- Proof of pregnancy: presence of either a vaginal plug or sperm in vaginal smear is counted as gestation day 0 of pregnancy
- After successful mating each pregnant female was put in plastic cages and nesting materials were added - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose concentrations were verified weekly. One sample for analysis was taken from the center of each dosing formulation prepared weekly during the in-life phase of the study. The mean concentrations for the Group II-500 mg/kg, Group III-1000 mg/kg, and Group IV-2000 mg/kg solutions were 67.5 mg/mL, 134.6 mg/mL, and 267.2 mg/mL, respectively. On average, males from Groups I-IV were dosed with 2.4, 2.3, 2.3 and 2.4 mg/mL of test substance, respectively. Females from Groups I-IV were dosed with an average of 1.8 mg/mL of test substance.
- Duration of treatment / exposure:
- Males and females were dosed for 14 days prior to mating. Males were dosed for another 14 days during mating, for a total of 28 days. Females were dosed through mating and until one day prior to termination (lactation Day 4 for those that delivered and Study Day 53 for those that did not deliver).
- Frequency of treatment:
- Daily as described above
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 500, 1000, 2000 mg/kg daily
Basis:
actual ingested
- No. of animals per sex per dose:
- Ten males and ten females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on a range finder test and a pretest
- Rationale for animal assignment (if not random): Random
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for males. Body weights for females were recorded on Days 7 and 14, and on Gestation Days 0, 4, 7, 11, 14, 17 and 20, and on Lactation Days 1 and 4. Body weights of pups were recorded on Lactation Days 1 and 4. Body weights were also recorded at the time of discovery for animals that died during the study.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes, food consumption was recorded weekly through the termination of the study with the exception of the cohabitation period.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not applicable
- Time schedule for examinations: Not applicable - Litter observations:
- Parturition and Litter Observations: The day parturition was complete was considered Lactation Day 0. When birth was completed, the litters were sexed, examined for gross malformations, and the number of stillbirths and live pups was recorded. The pups were individually marked for identification. Any changes or abnormalities in nesting or nursing behavior were recorded. Body weights for the pups were recorded on Lactation Days 1 and 4, and they were re-sexed at that time. Pups were observed daily for general appearance, behavior and survival.
- Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were sacrificed and evaluated on day 28.
- Maternal animals: All surviving animals were sacrificed and examined on lactation day 4 or for those not giving birth, study day 53.
GROSS NECROPSY/HISTOPATHOLOGY/ORGAN WEIGHTS
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]A gross necropsy examination was conducted on each adult animal at the time of discovery after death or at time of sacrifice. The necropsy included gross observations of external surfaces and all orifices, and gross observations of thoracic and abdominal cavities and their viscera. Special attention was paid to the organs of the reproductive system. The number of corpora lutea was recorded. The testes and epididymides of all sacrificed males and ovaries with oviducts of the sacrificed females were carefully removed, trimmed, and weighed. Ovaries with oviducts, testes, epididymides and accessory sex organs, and all organs showing macroscopic lesions were preserved. Tissues were weighed as soon as possible to avoid dehydration of the tissues. The liver, kidneys, thymus, spleen, brain and heart from five adult males and females randomly selected from each group were carefully removed, trimmed and weighed. The following tissues were preserved in 10% neutral buffered formalin: all gross lesions or tissues showing abnormalities, brain (cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestine (duodenum, jejunum, ileum, caecum and colon including Peyer’s patches), liver (sections of 2 lobes), kidneys, adrenals, spleen, heart and aorta, thymus, thyroid, trachea and lungs (including bronchi, preserved by inflation with fixative and then immersion), ovaries with oviducts, uterus, urinary bladder, lymph nodes (mesenteric and submandibular), peripheral nerve (sciatic or tibial) in close proximity to the muscle, and bone marrow.
A full histopathologic examination on all tissues saved from five males and five females from the control (Group I) and high-dose (Group II) groups and on all tissues saved from any animal which died on study. Special emphasis was put on the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure.
Observations for morbidity and mortality were made twice daily, and observations for pharmacologic and/or toxicologic effects were made once daily until study termination. General clinical observations included but were not necessarily limited to evaluation of skin, fur, eyes and mucous membranes, respiratory and circulatory effects, autonomic effects (salivation, lacrimation, excessive urination and diarrhea), central nervous system effects (tremors and convulsions), changes in the level of activity, gait and posture, reactivity to handling or sensory stimuli, altered strength and stereotypies or bizarre behavior (e.g., self mutilation, walking backwards). The nature, onset, severity, and duration of all gross or visible pharmacologic and/or toxicologic effects were recorded. Detailed clinical observations were made weekly in the same manner as pretest. - Statistics:
- The findings were evaluated in terms of the observed effects, necropsy, and microscopic findings. The evaluation includes the relationship between the dose of the test substance and the presence or absence, incidence and severity of abnormalities, including gross lesions, identified target organs, infertility, clinical abnormalities, affected reproductive and litter performance, body weight changes, effects on mortality and any other toxic effects. Accepted statistical methods were employed where appropriate, including one-way analysis of variance (ANOVA) and Dunnett’s t-test to identify differences from control when identified by ANOVA.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Seven animals, all but one in 2000 mg/kg dose
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Sporadic
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Sporadic
- 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:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): On Day 7, Group IV-2000 mg/kg male body weights were significantly lighter than Group I-Control (p=0.0435) and on Day 28, Group II-500 mg/kg male body weights were significantly lighter than Group III-1000 mg/kg rats (p=0.0191). There were no other significant differences between the groups for the male body weights or the body weight changes. For the female body weights, on Gestation Day 20 and Lactation Day 1, the body weights of the para females in Group III were significantly lighter than those of the Group I rats (p=0.0515 and 0.0086). Group IV nulliparous females had significantly less body weight change from the presumed Gestation Day 0 to Study Day 53 than Group I nulliparous females (p=0.0013). There were no other significant differences between groups for female body weights or body weight changes.
Among male food consumption amounts, from Days 7 through Day 14, animals from Group II-500 mg/kg consumed significantly more food than animals in Group IV-2000 mg/kg (p=0.0379). There were no other significant differences among food consumption amounts for males between groups. Among female food consumption amounts, rats in Group IV-2000 mg/kg consumed significantly less food for Days 0-14 than animals in Group I-Control (p=0.0103 and 0.0391). There were no other significant differences among food consumption amounts for females between groups.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): Dose concentrations were verified weekly. One sample for analysis was taken from the center of each dosing formulation prepared weekly during the in-life phase of the study. The mean concentrations for the Group II-500 mg/kg, Group III-1000 mg/kg, and Group IV-2000 mg/kg solutions were 67.5 mg/mL, 134.6 mg/mL, and 267.2 mg/mL, respectively. On average, males from Groups I-IV were dosed with 2.4, 2.3, 2.3 and 2.4 mg/mL of test substance, respectively. Females from Groups I-IV were dosed with an average of 1.8 mg/mL of test substance.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There were 4, 4, 7 and 3 females in Groups I – IV, respectively, that had successful births. Little difference is apparent in conception rates, number of pups delivered or incidence of stillborn pups when control and high-, mid- and low-dose groups are compared. Corpora lutea counts at necropsy are presented in Table 14. There were no significant differences in corpora lutea counts among groups.
ORGAN WEIGHTS (PARENTAL ANIMALS): There were no statistically significant differences among groups in weights of male organs. For females, there were no statistically significant differences among groups in the weights of female organs with one exception. The adrenal glands of Group III-1000 mg/kg females were significantly lighter than the adrenal glands of Group IV-2000 mg/kg (p=0.0311).
GROSS PATHOLOGY (PARENTAL ANIMALS): For males that were terminally sacrificed on schedule (Day 29), the only findings related to mottled kidneys found in nine animals among all four groups and one animal in Group II-500 mg/kg with an abnormally small right testicle. For the two males from Group IV-2000 mg/kg that died during the study, both had extreme gas in the stomach and one had discolored lymph nodes, matted hair around muzzle, gas in the intestines and expanded stomach dermal tissue. For para females that were sacrificed on schedule (Lactation Day 4), there were no observable abnormalities for any animal in any group. For nulliparous females that were sacrificed on schedule (Study Day 53), one animal had a flattened dorsal kidney, one animal had a flattened dorsal kidney and uterine horns filled with fluid and one animal had uterine horns filled with fluid. For the five females that died on study, abnormal findings included discolored lungs, liver and spleen, and the contents of the stomach, chest cavity, mouth, uterus, and small intestine.
HISTOPATHOLOGY (PARENTAL ANIMALS): The histopathology report concluded “No histologic test article related lesions were observed in this study. The reproductive organs of treated rats were similar to those of control rats. Several treated rats that died on study were highly suspect of aspiration of gavage material (two Group 4 males, three Group 4 females, and one Group 2 female). A number of spontaneous lesions commonly observed in rats were diagnosed. These lesions occurred in treated and control rats of both sexes and are not considered to be test article related. ” The report specified that of the rats which had died on test, “Some animals had good evidence of aspiration of the gavage material (inflammation in trachea and lungs), while others were only suspicious, but highly suspect of aspiration.”
OTHER FINDINGS (PARENTAL ANIMALS): For males, there were no significant differences between groups for any of the hematology parameters analyzed. For females, Group IV-2000 mg/kg white blood cells were significantly lower than Group II-500 mg/kg or Group III-1000 mg/kg (p=0.0020). There were no significant differences between groups for males or females for prothrombin and activated partial thromboplastin times. There were no significant differences between groups in the male serum chemistry data. For females, Group II-500 mg/kg total bilirubin was significantly lower than Group I-Control (p=0.0482). Group III potassium was significantly higher than Group II (p=0.0274). There were no other significant differences. No significant effects were observed in the functional observational battery or motor activity.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
Results: P1 (second parental generation)
General toxicity (P1)
- Clinical signs:
- no effects observed
Effect levels (P1)
- Remarks on result:
- not determinable due to absence of adverse toxic effects
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)
CLINICAL SIGNS (OFFSPRING): Daily observations of the litters revealed no observable abnormalities except for instances of pups not found or being found dead. On Lactation Day 1, one pup in Group III-1000 mg/kg was found thin and pale.
BODY WEIGHT (OFFSPRING): For Lactation Day 1 mean litter weights, Group III-1000 mg/kg was significantly lighter than any of the other groups and Group IV-2000 mg/kg weights were significantly heavier than Group I-Control (p=0.0001). For Lactation Day 4 mean litter weights, Group IV was significantly heavier than any of the other groups (p=0.0001).
Effect levels (F1)
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Results: F2 generation
General toxicity (F2)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Other effects:
- no effects observed
Developmental neurotoxicity (F2)
- Behaviour (functional findings):
- no effects observed
Developmental immunotoxicity (F2)
- Developmental immunotoxicity:
- no effects observed
Effect levels (F2)
- 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
Parturition and Litter Observations: Group birthing information is summarized below.
Group |
% Conception |
% Successful |
Mean # |
Mean Live |
Mean |
|
Delivery |
Pups |
Pups |
Stillborn |
|||
|
|
|||||
I-Control |
40.0% |
100% |
16 |
16 |
0 |
|
II-500 mg/kg |
44.4% |
100% |
15 |
15 |
0 |
|
III-1000 mg/kg |
70.0% |
100% |
15 |
14 |
1 |
|
IV-2000 mg/kg |
57.1% |
75%* |
14 |
14 |
0 |
Group means for individual pup body weights on Lactation Days 1 and 4 are summarized below:
Group |
Lactation Day 1 Means |
Lactation Day 4 Means |
Gain |
I-Control |
92.7 |
132.2 |
39.5 |
II-500 mg/kg |
94.9 |
123.0 |
28.0 |
III-1000 mg/kg |
82.6 |
121.9 |
39.3 |
IV-2000 mg/kg |
95.3 |
146.2 |
50.9 |
Weights are in grams |
|
|
|
A summary table of the reproductive measurements is shown below:
Observation |
Group I |
Group II |
Group III |
Group IV |
Pairs started (N) |
10 |
9 |
10 |
8 |
Females showing evidence of copulation (N) |
6 |
9 |
10 |
7 |
Females achieving pregnancy (N) |
4 |
4 |
7 |
3 |
Conceiving days 1 – 5 (N) |
4 |
7 |
8 |
6 |
Conceiving days 6 – 14 (N) |
2 |
2 |
2 |
1 |
Dams with live young born (N) |
4 |
4 |
7 |
3 |
Dams with live young at Day 4 (N) |
4 |
4 |
7 |
3 |
Corpora lutea/dam (mean) |
22.25 |
18.25 |
18.14 |
15.33 |
Live pups/dam at birth (mean) |
16 |
15 |
15 |
14 |
Live pups/dam at Day 4 (mean) |
15 |
14 |
13 |
14 |
Sex ratio (m/f) at birth (mean) |
0.63 |
0.97 |
0.59 |
0.84 |
Sex ratio (m/f) at Day 4 (mean) |
0.81* |
0.88 |
0.79* |
0.94 |
Litter weight at birth (mean) |
92.7 |
94.9 |
82.6 |
95.3 |
Litter weight at Day 4 (mean) |
132.2 |
123.0 |
121.9 |
146.2 |
Pup weight at birth (mean) |
6.4 |
6.5 |
6.2 |
6.8 |
Pup weight at Day 4 (mean) |
9.1 |
8.7 |
9.3 |
10.5 |
Dams with abnormal pups |
None |
None |
None |
None |
(N) - Number; m - Male; f - Female; * - mean includes one litter sexed on Day 1 instead of Day 4
Applicant's summary and conclusion
- Conclusions:
- No effects on either male or female reproductive performance was observed. Based on body weight gain reductions in the 2000 mg/kg bw/day group, the NOAEL was determined to be 1000 mg/kg bw/day.
- Executive summary:
The OECD 422 combined repeated dose study with reproductive and developmental toxicity screening was conducted to determine the subchronic toxicity to rats. Groups of rats were exposed by oral gavage to doses of 0, 500, 1000 and 2000 mg/kg bw/day of KGA Greens. Males were exposed for 28 days and females were exposed up through lactation day 4 or 53 days, after which surviving rats were sacrificed and necropsied. Observations of mortality and a suite of other examinations were conducted. Results show sporadic effects on various endpoints in the 2000 mg/kg bw/day high dose. At this 2000 mg/kg bw/day level the test substance appeared to be so irritating or distasteful that the animals tended to struggle and/or resist dosing, which in turn led to deaths likely caused by aspiration of gavaged material. No significant dose-related effects were observed in the 500 and 1000 mg/kg bw/day doses. No significant effects was observed at any dose on male or female reproductive performance. The NOAEL was determined to be 1000 mg/kg bw/day based on sporadic weight gain reductions in the maternal generation.
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