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EC number: 224-832-0 | CAS number: 4511-42-6
- 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
![](https://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Toxicity of lactide in dogs after 2 and 13 weeks of daily oral dosing
- Author:
- Hebert C.D. et al.
- Year:
- 1 999
- Bibliographic source:
- Food and Chemical Toxicology, 37. pp. 335-342
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
- Deviations:
- not specified
- Principles of method if other than guideline:
- Doses for the 13-wk study were selected based on the results of a 2-week study. In the 13-wk study, four dogs per sex were assigned to each of four treatment groups (dosed with lactide at 0, 4, 20 and 100 mg/kg body weight/day). Each dog received daily oral doses of one to six gelatin capsules containing lactide. Doses were administered at approximately 1 hr after feed was withdrawn, and at approximately the same time each day for 13 weeks. Control dogs received the same number of empty capsules as dogs of the corresponding sex in the highest dose group. Doses were calculated based on the body weight of each dog during the previous week.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- (3S-cis)-3,6-dimethyl-1,4-dioxane-2,5-dione
- EC Number:
- 224-832-0
- EC Name:
- (3S-cis)-3,6-dimethyl-1,4-dioxane-2,5-dione
- Cas Number:
- 4511-42-6
- Molecular formula:
- C6H8O4
- IUPAC Name:
- 3,6-dimethyl-1,4-dioxane-2,5-dione
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): lactide; 18:1 mixture of L-lactide (CAS no. 4511-42-6): m-lactide (CAS no. 13076-19-2)
- Lactide was manufactured and provided by Cargill, Inc USA
- bulk chemical stored at -20°C
For dose administration:
- removal from -20°C, 2 hours to reach ambient temperature
- lactide was loaded into 0.5 oz gelatin capsules
- each capsules contained between 0.1 g and 4 g of lactide
- no filling material was used to fill those capsules that contained less than 4g of chemical
- Capsules were prepared weekly, were stored on capsule boards, refrigerated in plastic bags containing desiccant
--> a prior stability study indicated that lactide was stable for at least 14 days when stored under these conditions
- Capsules were removed from refrigerator and allowed 2 hours to reach ambient temperature before dose administration
Test animals
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc ( Madison, WI, USA)
- Age at study initiation: ranged from 5 to 10 months
- Fasting period before study: 1 hour before dosing
- Housing: individual housed in stainless-steel cages on racks and were exercised at least twice weekly throughout the quarantine and study period
- Diet (e.g. ad libitum): dogs were fed Certified Canine Chow 5007 (PMI Feeds, Inc) for approximately 2 hours each day
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26°C
- Humidity (%): 35 - 85%
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: capsule
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- Each dog received daily oral doses of one to six gelatin capsules containing lactide. Doses were administered at approximately 1 hr after feed was withdrawn, and at approximately the same time each day for 13 weeks.
Control dogs received the same number of empty capsules as dogs of the corresponding sex in the highest dose group. Doses were calculated based on the body weight of each dog during the previous week. - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Single daily dose
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 4 mg/kg bw/day (actual dose received)
- Remarks:
- low dose
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Remarks:
- mid dose
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- high dose
- No. of animals per sex per dose:
- 4
- Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- Observations:
- Dogs were observed twice daily for mortality or moribundity.
- Cageside observations were performed daily, approximately 1 hr after dosing.
- Once a week, each dog was removed from its cage and examined closely for detailed clinical signs of toxicity.
- Throughout each study:
dogs were weighed weekly, and food consumption was measured once a week over a 2-hour period.
Clinical pathology:
- blood and urine samples were obtained from each dog for clinical pathology and urinalysis determinations during quarantine, during week 5 and 9, and within 3 days prior to terminal sacrifice
Dogs were fasted overnight prior to blood collection for haematologic, clinical chemistry and coagulation analyses
Haematologic analyses included:
total leucocyte count, erythrocyte count, haemaglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count and differential leucocyte count. Reticulocyte counts and red blood cell morphology were evaluated.
Clinical chemistry analysis included:
By using a Roche Cobas Fara clinical chemistry analyser: blood urea nitrogen, creatinine, serum glucose, serum aspartate aminotransferase, serum alanine aminotransferase, alkaline phosphatase, glutamyl transferase, sodium, potassium, chloride, calcium, inorganic phosphate, total protein, albumin, albumin/total protein ratio, total bilirubin and cholesterol.
Coagulation analyses included:
Prothrombin time and activated partial prothrombin time, fibrinogen
Urine analyses included:
Urine specific gravity, urine microscopic sediment, urine pH, ketones, protein, glucose, bilirubin and occult blood - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- - Groups means and standard deviations for: body weights, food consumption, clinical pathology parameters, for terminal body weights and for absolute and relative organ weights
- Body weights, food consumption and clinical pathology parameters were evaluated by two-way repeated ANOVA, and if significant by Dunnett´s test
- Mean body weights, mean organ weights and organ/body, organ:brain ratios for each treated group were compared to those of the control group by a two-tailed Students t-test for each sex
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Emesis once in each of two female dogs (one in the 0 mg/kg and one in the 100 mg/kg group during week 9). Bloody diarrhoea was seen once during week 6 in one female dog of the 100 mg/kg group
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Emesis once in each of two female dogs (one in the 0 mg/kg and one in the 100 mg/kg group during week 9). Bloody diarrhoea was seen once during week 6 in one female dog of the 100 mg/kg group
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- stomach foci in one male/female from the 100 mg/kg , and one female from the 4mg/kg dose group
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- moderately severe ulceration of the stomach mucosa seen in one female dog of the high dose group
- Histopathological findings: neoplastic:
- no effects observed
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- (systemic)
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse systemic effects observed at the highest tested dose 100 mg/kg/day
- Dose descriptor:
- LOAEL
- Remarks:
- (local)
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: gastrointestinal irritation
- Dose descriptor:
- NOAEL
- Remarks:
- (local)
- Effect level:
- 20 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: gastrointestinal irritation
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Incidence of gross lesions in dogs treated for 13 weeks with oral doses of lactide | ||||||
Dose group | 0 mg/kg | 4 mg/kg | 20 mg/kg | 100 mg/kg | ||
Males | ||||||
Stomach focus | 0 | 0 | 0 | 1 | ||
Females | ||||||
Stomach focus | 0 | 1 | 0 | 1 |
Incidence= number of dogs in a given dose group with a given lesion. n=4 for all dose groups
Applicant's summary and conclusion
- Conclusions:
- Lactide acts primarily, if not only, as an irritant after oral administration. 13 week NOAEL is 100 mg/kg bw/d.
- Executive summary:
In a subchronic toxicity study lactide (18:1 mixture of l-lactide and m-lactide) was administered to 4 beagle dogs/sex/dose by capsule at dose levels of 4, 20, 100 mg/kg bw/day for 13 weeks.
The only apparent toxic effect at 100 mg/kg/day was gastrointestinal irritation. Therefore, the local LOAEL is 100 mg/kg/d. No systemic effects were reported at 100 mg/kg/d. Thus, the systemic NOAEL for orally administered lactide under the conditions in this study was considered to be 100 mg/kg/day.
This subchronic study in dog is acceptable and satisfies the principle requirement for a subchronic oral study similar to OECD 409 in dog.
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