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EC number: 939-424-4 | CAS number: 1469983-44-5
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16 July 2003 to 11 January 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, England.
- Age at study initiation: 6 weeks
- Weight at study initiation: Males 154-169g; Females: 149-166g.
- Housing:
Pre-mating: 1/sex/cage, polypropylene cages with stainless steel grid tops and solid bottoms
Mating: 1:1, polypropylene cages with stainless steel grid tops and solid bottoms
Post-mating: female 1/sex/cage, solid-bottom cages with white paper tissue as nesting material
- Diet (e.g. ad libitum): Al libitum, Rat and Mouse Breeder Diet No.3 (Ground) SQC (Special Diets Services Ltd. Stepfield, Witham, Essex, UK)
- Water (e.g. ad libitum): Ad libitum, tap-water
- Acclimation period: 12 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 43-60
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: feed
- Vehicle:
- acetone
- Details on exposure:
- DIET PREPARATION
- Frequency of preparation of diet: fresh diets were prepared weekly during the study.
- A pre-mix was made by mixing the test item dissolved in acetone with appropriate amounts of Rat and Mouse Breeder Diet No.3 (Ground) SQC (RM3 diet). The high- and intermediate-dose diets were made by mixing appropriate amounts of pre-mix with untreated RM3 diet. The low-dose diet was made by diluting the intermediate-dose diet with appropriate amounts of untreated RM3 diet. The control diet was made using a pre-mix that was made using acetone alone.
- Storage temperature of food: Ambient temperature. - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: 7 days in first attempt. If not successful, followed by a second period of 7 days with a male of proven fertility
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- No further matings after two unsuccessful attempts.
- After successful mating each pregnant female was caged individually. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Diet prepared for Week 2 and Week 4 of treatment was sampled. Triplicate samples were withdrawn from each formulated diet, including the Control formulation. The samples were analyzed by Inveresk Toxicology Support Laboratory using a method previously validated in the Inveresk laboratory under a separate protocol and contract (Inveresk Project No. 421274).
Concentrations were within 10% of nominal concentrations and the low coefficient of variation (<2.5%) showed homogeneous distribution of the test item in the diets. The analytical method is not specified in the report. - Duration of treatment / exposure:
- Males: 4 weeks overall, starting 2 weeks prior to mating until termination
Females: 2 weeks prior mating, through mating until termination after Day 4 of lactation. - Frequency of treatment:
- Continuously via the diet
- Details on study schedule:
- - The age of the animals at the start of mating was 9-10 weeks.
- Remarks:
- Doses / Concentrations:
0, 46, 271 and 1324 mg/kg bw/day
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
0, 500, 3000 and 15000 ppm
Basis:
nominal in diet - No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on results of a 7-day dose range finding study
- Positive control:
- Not relevant
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Weekly
- Cage side observations checked included: Posture/condition on first approach (animal undisturbed) checking for: Prostration, Lethargy, Writhing, Circling, Breathing abnormalities, Gait abnormalities, Tremor, Fasciculation, Convultions, Biting (of cage components or self mutilating), Vocalisations, Piloerection. Furthermore, ease of removal from cage, body temperature, condition of the coat, presence of salivation, overall ease of handling
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All the animals were examined for reaction to treatment on each day. The nature, onset and intensity of any signs were recorded.:
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
Male body weights were recorded once during the week prior to the commencement of treatment and once weekly thereafter until termination.
Female weights were recorded once during the week prior to the commencement of dosing, and weekly thereafter until the start of the mating period, and then on Day 0 of gestation (the day of detection of a positive mating sign) followed by Days 7, 14 and 20 of gestation, and then Days 1 and 4 of lactation (where Day 0 = the day of parturition).
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
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
Water consumption was monitored by visual inspection of the water bottles on a weekly basis throughout the study. - Oestrous cyclicity (parental animals):
- Stage of oestrous cycle determined daily in vaginal smears from pairing until mating had occurred and at necropsy.
- Sperm parameters (parental animals):
- Parameters examined in P male parental generations: testis weight, epididymis weight
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number of live and dead pups, sex of pups, presence of gross anomalies, examined for the presence of milk in the stomach.
Litters were weighed en masse (by sex) on days 1 and 4 of lactation.
GROSS EXAMINATION OF DEAD PUPS: no
Any deficiencies in lactation or maternal care were recorded. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: Following 4 weeks of treatment for males all adult animals were sacrificed by exposure to carbon dioxide, followed by exsanguination.
- Maternal animals: After Day 4 of lactation (Days 5-8 of lactation) for females, all adult animals were sacrificed by exposure to carbon dioxide, followed by exsanguination.
GROSS NECROPSY
All adults were subject to a detailed necropsy under the guidance of a veterinary pathologist. The necropsy consisted of an external and internal
examination. All gross lesions were recorded in terms of location, size, shape, colour, consistency and number.
HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were weighed:
Adrenals, brain, epidymides, heart, kidneys, liver, lung, ovaries, pituitary, prostate, spleen, Submaxillary Salivary Gland, testes, thymus, thyroids with Parathyroid, uterus.
The following tissues were prepared for microscopic examination:
Abnormal tissue, adrenals, aorta, brain, epididymides, eyes gastrointestinal tract (stomach, duodenum, jejunum, ileum, caecum, colon, rectum), heart, optic nerve, kidneys, liver, lung, mesenteric lymph node, oesophagus, ovaries, pancreas, pituitary, prostate, sciatic nerve, seminal vesicle, skin+mammary gland, spinal cord, spleen, sternum, submandibular lymph node, Submaxillary Salivary Gland, testes, thigh muscle, thymus, thyroids with Parathyroid, trachea, urinary bladder, uterus, vagina. - Postmortem examinations (offspring):
- SACRIFICE
- Pups were sacrificed by injection of sodium pentobarbitone. A random order was used for the necropsy of the adult animals and the pups were sacrificed at the same time as their mother - After day 4 of lactation (day 5-8 of lactation).
- These animals were subjected to postmortem examinations. The pups were examined for externally visible abnormalities
GROSS NECROPSY
- Gross necropsy consisted of external examinations.
HISTOPATHOLOGY / ORGAN WEIGTHS
Not performed. - Statistics:
- Selected neurotoxicity, body weight, food consumption, haematology and clinical chemistry data were subjected to analysis of variance or the Kruskal- Wallis non-parametric analysis. Organ weights were analysed as above and by one-way analysis of covariance (ANCOVA) using the terminal kill body weight as covariate. Histological incidence data were analysed using Fisher’s Exact Probability test.
Pairwise comparisons were made using Fisher’s F-protected LSD method via Student’s t-test, or by chi-squared protected z-test (the non-parametric equivalent of Student’s t-test), and were only performed against the Control group.
All statistical tests were two-sided and performed at the 5% significance level. - Reproductive indices:
- Fertility Index (male) = Number Siring a litter / Number paired
Fertility Index (female) = Number Pregnant / Number paired
Gestation Index = Number bearing live pups / Number pregnant
Birth Index = Total number of pups born (live and dead) / Number of implantation scars - Offspring viability indices:
- Viability Index = Number of pups live on Day 4 of lactation / Number live on Day 0
Live Birth Index = Number of pups live on Day 0 of lactation / Total number born (live and dead) - 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:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- effects observed, treatment-related
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 271 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Increased liver weights and increased centrilobular hepatocyte hypertrophy in males and females in the highest dose
- 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:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 324 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: There were no treatment-related changes in reproductive parameters in any of the dose groups.
- Reproductive effects observed:
- not specified
- Conclusions:
- Toxicity to reproduction/developmental toxicity potential of Diacid 1550 was investigated in a combined 28-d repeated dose toxicity/reproscreening study that was performed in accordance with OECD422 and under GLP conditions. Diacid 1550 was administered orally via the diet at 0, 500, 3000, and 15000 ppm. There were no treatment-related changes observed in reproductive parameters in any of the dose groups. Therefore, the NOAEL for reproductive parameters was considered 15000 p.p.m. (corresponding to 1324 mg/kg bw/day), under the conditions of this study.
- Executive summary:
This study was designed to provide initial information on possible effects on reproduction and/or development of Diacid 1550 in the rat after oral administration via the diet for at least weeks. The study was performed in accordance with OECD 422 and under GLP conditions.
Four groups of 10 male and 10 female Sprague-Dawley rats received Diacid 1550 itemviathe diet at a constant concentration of 0, 500, 3000 and 15000 p.p.m (corresponding to 0, 46, 271 and 1324 mg/kg bw/day). The males were treated for 2 weeks prior to mating, through until necropsy after at least 4 weeks of treatment. Females were treated for 2 weeks prior to mating, then through mating, gestation until at least Day 4 of lactation. The animals were monitored daily for any signs of ill health or reaction to treatment. Detailed functional observations were performed weekly, with additional functional observations performed on 5 males and 5 females per group on two occasions (pre-trial and in week 4 for males and during lactation for females). Blood samples were also taken from 5 males and 5 females per group for laboratory investigations. All adult animals were killed and subjected to a detailed necropsy examination after completion of treatment. Representative tissue samples were taken from all adults and a selection of tissues were weighed. Histopathology was conducted on tissues from 5 rats/sex from Control and High dose groups; the same animals that were used for laboratory investigations.Pups were examined externally.
At 15000 p.p.m., there was an increase in liver weights that was associated with an increase in centrilobular hepatocyte hypertrophy which was observed in 2/5 males and 4/5 females examined. Changes in liver function were demonstrated with an increase in alkaline phosphatase. Clinical chemistry at this level also revealed an increase in albumin in both sexes, a reduction in cholesterol and an increase in phosphate in females. Furthermore, in females kidney weight was markedly increased and spleen weight was markedly decreased. A decrease in thymus weights of females was also evident at this level.
At 3000 p.p.m., liver weight was also increased, although not statistically significant. An increase in the levels of alkaline phosphatase was also seen in both sexes. In females, there was an increase in albumin and a slight increase in phosphate, as well as a reduction in cholesterol. At 500 p.p.m. there was an increase in alkaline phosphatase in males, and reduced cholesterol in females. The reduction in cholesterol was dose-related. As the values are all within the historical ranges in Sprague-Dawley rats, they were considered not adverse (Jung-Min Lee et al., Laboratory Animal Research, 2012: 28(2), 115-121).
There were no obvious effects of treatment noted during neurotoxicity observations or on the mating performance.
There was no obvious effect of treatment on the mean number of implants, live young per litter or on litter survival as indicated by the birth index and viability index. At 15000 p.p.m, and to a lesser extent at 3000 p.p.m., there was a slightly reduced mean pup weight in males and females, reflecting the slightly larger number of live pups per litter at these levels. Group mean litter weights at both levels were comparable with Control. Group mean litter and pup weights at 500 p.p.m. were comparable to Control. Only minor findings such as pups cold and/or scattered, that are typical for pre-weanings were observed but have not been reported, these findings are retained in the study data.
In conclusion, based on increased liver weights and increased centrilobular hepatocyte hypertrophy in males and females at the highest does, the parental NOAEL was considered to be 3000 p.p.m., corresponding to 271 mg/kg bw/day, under the conditions of this study.. For reproductive parameters the NOEL was considered to be 15000 p.p.m., corresponding to 1324 mg/kg bw/day.
Reference
All clinical observations and necropsy findings were considered to be consistent with those normally seen in rats of this age and strain.
All clinical signs observed were those commonly noted during this type of study, and there were no significant differences in group incidence or between sexes.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Food consumption was marginally reduced in high-dose males on days 14 and 28.
No obvious treatment-related changes were seen in males or females prior to mating or during gestation and lactation.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
The nominal dose levels of 500, 3000 and 15000 p.pm. resulted in mean actual test substance intakes of 46, 271 and 1324 mg/kg bw/day, respectively
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There were no treatment-related changes in mating preformance. The duration of gestation was similar in all groups.
ORGAN WEIGHTS (PARENTAL ANIMALS)
At 15000 p.p.m., there was an increase in liver weight in both sexes. This increase was also evident at 3000 p.p.m., although statistical significance was not achieved at this level. At 15000 p.p.m., there was a slight but significant increase in the absolute weight of kidneys in females.
At 15000 p.p.m. in females, there was a decrease in spleen weight. A marginal reduction in the spleen weight in high-dose males did not reach statistical significance. There was a dose related reduction in absolute thymus weights in females which attained statistical significance at 15000 p.p.m. The absolute thymus weights in low- and intermediate-dose females were not statistically significantly different from Control.
GROSS PATHOLOGY (PARENTAL ANIMALS)
There were no obvious intergroup differences in either sex.
HISTOPATHOLOGY (PARENTAL ANIMALS)
Histological examination of the liver revealed centrilobular hepatocyte hypertrophy at 15000 p.p.m. in 2/5 males and 4/4 females examined.
There was no obvious effect of treatment on the mean number of implants, live young per litter or on litter survival as indicated by the birth index and
viability index.
BODY WEIGHT (OFFSPRING)
At 15000 p.p.m, and to a lesser extent at 3000 p.p.m., there was a slightly reduced mean pup weight in males and females, reflecting the slightly larger number of live pups per litter at these levels. Group mean litter weights at both levels were comparable with Control.
Group mean litter and pup weights at 500 p.p.m. were comparable to Control.
GROSS PATHOLOGY (OFFSPRING)
Only minor findings such as pups cold and/or scattered, that are typical for pre-weanings were observed but have not been reported, these findings are retained in the study data.
Not applicable
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 324 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
This study was designed to provide initial information on possible effects on reproduction and/or development of Diacid 1550 in the rat after oral administration via the diet for at least weeks. The study was performed in accordance with OECD 422 and under GLP conditions.
Four groups of 10 male and 10 female Sprague-Dawley rats received Diacid 1550 itemviathe diet at a constant concentration of 0, 500, 3000 and 15000 p.p.m (corresponding to 0, 46, 271 and 1324 mg/kg bw/day). The males were treated for 2 weeks prior to mating, through until necropsy after at least 4 weeks of treatment. Females were treated for 2 weeks prior to mating, then through mating, gestation until at least Day 4 of lactation. The animals were monitored daily for any signs of ill health or reaction to treatment. Detailed functional observations were performed weekly, with additional functional observations performed on 5 males and 5 females per group on two occasions (pre-trial and in week 4 for males and during lactation for females). Blood samples were also taken from 5 males and 5 females per group for laboratory investigations. All adult animals were killed and subjected to a detailed necropsy examination after completion of treatment. Representative tissue samples were taken from all adults and a selection of tissues were weighed. Histopathology was conducted on tissues from 5 rats/sex from Control and High dose groups; the same animals that were used for laboratory investigations.Pups were examined externally.
At 15000 p.p.m., there was an increase in liver weights that was associated with an increase in centrilobular hepatocyte hypertrophy which was observed in 2/5 males and 4/5 females examined. Changes in liver function were demonstrated with an increase in alkaline phosphatase. Clinical chemistry at this level also revealed an increase in albumin in both sexes, a reduction in cholesterol and an increase in phosphate in females. Furthermore, in females kidney weight was markedly increased and spleen weight was markedly decreased. A decrease in thymus weights of females was also evident at this level.
At 3000 p.p.m., liver weight was also increased, although not statistically significant. An increase in the levels of alkaline phosphatase was also seen in both sexes. In females, there was an increase in albumin and a slight increase in phosphate, as well as a reduction in cholesterol. At 500 p.p.m. there was an increase in alkaline phosphatase in males, and reduced cholesterol in females. The reduction in cholesterol was dose-related. As the values are all within the historical ranges in Sprague-Dawley rats, they were considered not adverse (Jung-Min Lee et al., Laboratory Animal Research, 2012: 28(2), 115-121).
There were no obvious effects of treatment noted during neurotoxicity observations or on the mating performance.
There was no obvious effect of treatment on the mean number of implants, live young per litter or on litter survival as indicated by the birth index and viability index. At 15000 p.p.m, and to a lesser extent at 3000 p.p.m., there was a slightly reduced mean pup weight in males and females, reflecting the slightly larger number of live pups per litter at these levels. Group mean litter weights at both levels were comparable with Control. Group mean litter and pup weights at 500 p.p.m. were comparable to Control. Only minor findings such as pups cold and/or scattered, that are typical for pre-weanings were observed but have not been reported, these findings are retained in the study data.
In conclusion, based on increased liver weights and increased centrilobular hepatocyte hypertrophy in males and females at the highest does, the parental NOAEL was considered to be 3000 p.p.m., corresponding to 271 mg/kg bw/day, under the conditions of this study.. For reproductive parameters the NOEL was considered to be 15000 p.p.m., corresponding to 1324 mg/kg bw/day.
Short description of key information:
Reproscreening study (OECD422): No effects observed on development or reproduction, NOAEL 1324 mg/kg bw/d (oral, rat)
Justification for selection of Effect on fertility via oral route:
The study is the only available study with regard to developmental toxicity/toxicity to reproduction and was performed according to OECD422 and under GLP-conditions.
Effects on developmental toxicity
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
In the reproscreening study no effects on development were observed.
Justification for classification or non-classification
Based on the available information from the reproscreening study, Diacid 1550 does not have to be classified ar reprotoxic/toxic to the development in accordance with the criteria outlined in Annex VI of 67/548/EEC and Annex I of 1272/2002/EEC.
Additional information
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