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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(2R)-2-(2-chlorophenyl)-2-hydroxyethanoic acid
EC Number:
444-040-0
EC Name:
(2R)-2-(2-chlorophenyl)-2-hydroxyethanoic acid
Cas Number:
52950-18-2
Molecular formula:
Hill formula: C8H7ClO3 CAS formula: C8H7CLO3
IUPAC Name:
(2R)-2-(2-chlorophenyl)-2-hydroxyacetic acid
Details on test material:
- Name of test material (as cited in study report): (R)-2-chloromandelic acid
- Physical state: white powder
- Analytical purity: 99.7 %
- Purity test date: 2001-01-12
- Lot/batch No.: CR-UY-002 (Mitsubishi Rayon) - 1S00175 (Sanofi-Synthélabo).
- Stability under test conditions: guaranteed by the sponsor
- Storage condition of test material: at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, Domaine des Oncins, 69592 L'Arbresle Cedex, France
- Age at study initiation: about 7 weeks
- Weight at study initiation: 211 to 258 g for males and 162 to 197 g for females.
- Fasting period before study: none
- Housing: individual
- Diet : controlled pelleted rodent diet (re. AO4C. 10, U.A.R.), ad libitum, analyzed for the presence of contaminants (bacteria, mycotoxins, organochlorine and organophosphate pesticides, heavy metals and nitroso derivatives) with a certificate of analysis supplied by the manufacturer.
- Water: free access to controlled tap water through automatic waterers. Water is analyzed twice a year for physical and chemical contaminants (Institut Bouisson Bertrand, 34000 Montpellier, France) and four times yearly' for bacteriological contaminants by the Analytical Department of Sanofi-Synthélabo Recherche.
- Acclimation period: at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 30-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.6% methylcellulose aqueous solution.
Details on oral exposure:
DIET PREPARATION
Preparation: prepared as an oral suspension in 0.6% methylcellulose aqueous solution by the Formulation Unit according to stability data.
Frequency of diet preparation:
- for dosages of 100 and 450 mg/kg per day (corresponding to concentrations of 15 and 45 mg/mL respectively), the suspension was prepared up to once a week, according to stability data,
- for the dosage of 1000 mg/kg per day (corresponding to the concentration of 100 mg/mL), the suspension was freshly prepared due to homogeneity problems.
Concentrations: 15, 45 and 100 mg/mL
Storage conditions: 2-80C.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis during the study: preparation control was performed once during the study under the responsibility of the Analytical department at Sanofi-Synthélabo Recherche, Montpellier. The identity and concentration of the molecule in the vehicle were determined.
Duration of treatment / exposure:
33 to 34 days, from Day 1 of the study, the last treatment day being the day before necropsy.
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0; 150; 450; 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
control and high dose group: 10 males and 10 females;
other dosing groups: 5 males and 5 females;
Control animals:
yes
Details on study design:
Post-exposure period: 2 weeks
Positive control:
not included

Examinations

Observations and examinations performed and frequency:
Examinations performed
Clinical examinations
Clinical signs
Frequency: at least twice daily, particularly after treatment (week days), at least once daily (week-end and public holidays).
Animals concerned: all animals.
Clinical signs: date of onset and progression were recorded.
Method: visual observation. The use of camera (Panasonic S-VHS-C) was not necessary.

Detailed clinical observations
Frequency: once before the first exposure (to allow for within-subject comparisons), and at least once a week thereafter, for detailed clinical observations. For each period, observations lasted for two days: first day for males and the next day for females. However, for technical reasons, only the first day of each observation period is reported in the tables of results.
Animals concerned: all animals.
Method: the observations were made outside the home cage in a standard arena. They consisted in visual observation and evaluation of response to handling. The following parameters were scored: spontaneous activity, gait, tonus, palpebral closure, grooming, vocalization, clonic or tonic movements, stereotypies, bizarre behavior, removal from cage, handling in hand, changes in skin, für, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern).

Neurofunctional tests
Frequency: in the fourth exposure week, on days 26 and 27 (reflexes and grip strength: day 26 for males and day 27 for females - motor activity: day 27 for males and day 26 for females). Like for clinical examinations, the date mentioned in the tables of results is day 26.
Animals concerned: all animals.
Method: reflexes of different types (dick, corneal, pupillary, blinking, proprioceptive and righting), assessment of grip strength and motoractivity assessment were conducted.

Mortality
Post-mortem examinations were performed on the decedent.

Body weight changes
Frequency: on day -1 then weekly prior to drug administration.
Animals concerned: all animals.
Parameter: body weight (g).

Food intake
Frequency: weekly.
Animals concerned: all animals.
Parameters:
- Quantity of food distributed (g): 300 g (not mentioned in the report)
- Quantity of food remaining (g): weighed (not mentioned in the report)
- Quantity of food consumed (g/24h): calculated.

Hematology analysis
Hematology
Sampling days: on day 30 prior to drug administration, and on day 50 (recovery phase).
Animals concerned:
- all animals
- animals were fasted for approximately 16 ± 2 hours
- animals were anesthetized in a device with an isoflurane mixture (O2 6 liters, N20: 0.6 liters, Isoflurane: 2%)
Method:
- Sampling site: retro-orbital sinus
- Volume of blood: 0.5 mL
- Anticoagulant: EDTA
- Device: analysis on fresh blood by Technicon H*1EC (Bayer Diagnostics) and Sysmex R 2000 for reticulocytes.
- Blood smears: prepared, stained by Wright's method. Examination was not necessary.

Parameters
Erythrocytes (total RBC)
Hemoglobin (Hb)
Packed cell volume (PCV)
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin' (MCH)
Mean corpuscular hemoglobin concentration (MCHC)
Leukocytes (total WBC)
Differential leukocyte count (absolute value)
Thrombocytes (platelets)
Reticulocytes (percentage)

Coagulation
Sampling day: on days 34 (males) and 35 (females) for terminal sacrifice at the end of treatment and on day 51 for sacrifice at the end of the recovery phase.

Animals concerned: all animals.
Method:
- Sampling site: abdominal aorta
- Volume of blood collected: 1.8 mL
- Anticoagulant: trisodic citrate (3.8% - 1V/9V of blood)
- Device: ACL 3000 (Instrumentation laboratory)

Parameters
Prothrombin time
Activated partial thromboplastin time (APIT)
Thrombin clotting time
Prothrombin level
Fibrinogen level

Biochemistry analysis
Plasma biochemistry
Sampling days: on day 33 prior to drug administration, and on day 50 (recovery phase).
Animals concerned: all animals
- animals were fasted for approximately 16 ± 2 hours
- animals were anesthetized in a device (Minerve - Gentre Evolic) with an isoflurane mixture (O2: 6 liters, N2O: 0.6 liters, Isoflurane: 2%)
Method:
- Sampling site: retro-orbital sinus
- Volume of blood: 1.5 mL
- Anticoagulant: lithium heparinate
- Device: Hitachi 717 automatic analyzer (Boehringer).
Parameters Units
Glucose mmol/L
Urea mmol/L
Creatinine
Total proteins
Albumin
Globulins
Albumin/globulins
Triglycerides
Total cholesterol
Alanine aminotransferase (GPT/ALT)
Aspartate aminotransferase (GOT/AST)
Alkaline phosphatases (ALP)
Gamma-glutamyl transpeptidase (GGT)
Sodium
Potassium
Chloride
Inorganic phosphate
Calcium

Urinalysis
Sampling days: on day 28 prior to drug administration.
Animals concerned:
- the last 5 surviving animals/sex/group,
- animals were fasted for approximately 18 hours after oral administration (gavage) of
approximately 10 mL/kg tap water on the previous day.

Method:
- Urine samples were collected over an approximately 1 8-hour period in metabolism cage.
- Volume was measured.
- Color and clearness were appraised.

Examination by multi-reagent strips
Method:
- Multi-reagent strips: Multistix 10 SG (Ames Division, Miles Laboratories).
- Device: Clinitek 200 automatic analyzer (Miles Laboratories, Inc.).

Parameter
pH
Proteins
Ketone bodies
Bilirubins
Urobilinogen
Specific gravity
Glucose
Leukocytes
Blood
Nitrite
Sacrifice and pathology:
Necropsy
Final sacrifice: necropsy on days 34 (males) and 35 (females) for terminal sacrifice of the main study and an day 51 for the end-of-recovery sacrifice
- Animals concerned: all surviving animals
- Animals were not fasted overnight prior to sacrifice at the end of the treatment period and were
fasted overnight prior to sacrifice at the end of the recovery phase.
- Sacrificed animals were exsanguinated while under general anesthesia with pentobarbital sodium, 1 mL/kg, I.P. (Pentobarbital, Sanofi Santa Animale).

Macroscopv:
- Animals concerned: all animals.
- Complete macroscopic examination.
- Organs and tissues preserved:.
- All macroscopically abnormal organs and tissues were preserved, even if not scheduled in the table below (with, when possible, local lymph node if a tumor mass was suspected).
Organ weights:
- Animals concerned: all animals, except premature decedents.
- Organs weighed: For technical reasons, paired organs were weighed separately, with the exception of submandibular salivary glands

Light microscopy:
- Animals concerned: all animals.
- Organs and tissues examined: see table below, column LIGHT MIC..
- from all animals of groups 0 and 3 sacrificed at the end of treatment and from animals sacrificed in moribund condition or found dead during the study,
- from animals of groups 0 and 3 kept for recovery phase,
- from animals of groups 1 and 2 according to die modifications observed in the high dosage group, at the pathologist's request.

Femoral bone marrow smear
- Animals concerned: all animals.
- Smears were performed just after exsanguination

Organ list for microscopy:
Skin/subcutaneous tissue
Mammary gland
Liver
Spleen
Kidneys
Adrenal glands
Thymus
Heart
Lung
Bronchial lymph node
Urinary bladder
Ovaries
Uterine horns
Cervi
Vagina
Testes
Epididymides
Prostate
Seminal vesicles
Aorta
Sciatic nerve, right
Skeletal muscle (crural)
Popliteal lymph nodes
Pancreas
Esophagus
Tongue
Stomach (non glandular)
Stomach (glandular)
Duodenum
Jejunum
Ileum
Cecum
Colon
Rectum
Mesenteric lymph node
Submandibular salivary glands
Parotid gland, right
Cervical esophagus and trachea
Thyroid glands
Parathyroid glands
Trachea
Eyes
Optic nerves
Lacrimal glands
1-larderian glands
Brain
Pituitary gland
Spinal cord
Femoral bone marrow
Femoral-tibial joint
Larynx
Inner ear, right
Nasal turbinates
Diaphragm
Statistics:
Statistical package: IMSL Library, Houston, Te as, USA, used for programming the following statistical methods.

Parametric methods: used when the theoretical distribution of data was normal.
- Step 1 - Homogeneity of intergroup variances: assessed using the Levene's test. If the test was not significant, analysis continued with a one-way ANOVA (step 2). If the test was significant, analysis continued with the Snedecor's F test by comparing each treated group with the control group. If the F test was not significant, analysis continued with the Student's t test (step 3). If the F test was significant, analysis continued with the Student Welch's test (step 3).

- Step 2 - Equality of intergroup means: assessed using a one-way ANOVA (group).
If the test was not significant, intergroup means were considered as equal. If the test was significant, analysis continued with the Bonferroni's test (step 3).

-Step 3 - Pair-wise comparisons of means between the treated groups and the control group: performed using either the Bonferroni's test, or the Student's t test, or the Student Welch's test. If the test was not significant, means of the treated group were considered as equal to those of the control group. If the test was significant, means of the treated group were different from those of the control group.

Non-parametric methods: used when the theoretical distribution of data was not normal.
- Equality of intergroup rank means: assessed using the Kruskal Wallis' test. If the test was not significant, rank means were considered as equal. If the test was significant, analysis continued.
- Pair-wise comparisons of rank means between the treated groups and the control group: assessed using the Kruskal Wallis' test. If the test was not significant, rank means of the treated groups were considered as equal to those of the control group. If the test was significant, rank means of the treated groups were different from those of the control group.

Results and discussion

Results of examinations

Details on results:
Clinical signs and mortality
The following treatment-related clinical signs were observed:
- loud breathing:
- group 2 (450 mg/kg per day): in one male on days 33 and 34, and associated with hypothermia in the same animal on day 33,
- group 3 (1000 mg/kg per day): in three females, this sign lasted 2 to 5 days as from day 4, and then either disappeared or was associated with other signs preceding death; No evidence of associated or explanatory histopathological changes were noted in these animals, except for one female.

One female animal (group 3, 1000 mg/kg per day) was found dead on day 9, following several days of clinical signs indicative of a deterioration of health (dried blood on the muzzle, piloerection, hypothermia, soiled anogenital area and dyspnoea), marked weight loss (-24% after one week of treatment) and low food intake. However, examinations at necropsy showed that this female suffered from marked cervical curvature, which may have made gavage difficult, with possible misgavage trauma. Therefore, the final imputation of this death to the compound remains doubtful.
The following clinical signs were accidental or due to spontaneous pathology and were considered not to have interfered with the treatment:
- scab on the neck of one animal (group 2, 450 mg/kg per day) from day 19 to day 31,
- exophthalmia of the left eye in animals Nos. 9M (control), and 49M (group 3, 1000 mg/kg per day) on days 50 and 51 and in animal No. 47M (group 3, 1000 mg/kg per day) from day 33 to day 36. Corneal opacity was observed in the latter from day 37 to 51. These observations were due to blood puncture.
- wound on the left hindfoot in animal No. 58F (group 3, 1000 mg/kg per day). The wound was treated with BetadineTM.

Detailed clinical observations
Decreased respiratory rate was observed on day 5 in animal No. 58F (group 3, 1000 mg/kg per day) and on day 33 in animal No. 34M (group 2, 450 mg/kg per day). This change could be related to loud breathing noted in these animals. The statistically significant changes listed below were not considered to be treatment-related:
- minor increase in spontaneous activity in group 1 (150 mg/kg per day) males on day 33 and in group 3 (1000 mg/kg per day) females on day 47. This observation was not considered to be biologically significant.
- minor increase in urination in group 2 (450 mg/kg per day) males on days 19 and 26 and in group 1 (150 mg/kg per day) males on day 26, due to the absence of urination in most control males.

Neurofunctional tests
No treatment-related changes were observed.

Body weight
No treatment-related or possibly treatment-related changes were noted. The slightly lower absolute (g) and relative (%) body weight gain noted in group 3 (1000 mg/kg per day) females on day 35 (recovery period), with statistically significant difference when compared with controls, was attributed to the difference at D27 in mean body weight value between the five animals from groups 0 and the five animals from group 3 that were kept for the recovery phase (240.4 g in group 0 versus 223.2 g in group 3).

Food intake
No treatment-related or possibly treatment-related changes were noted, with the single exception of bw food intake in female No.58. The following variation was considered to be incidental and was not attributed to treatment:
- slightly high food intake in males from group 1 (150 mg/kg per day) on day 14; this variation was observed neither at the higher dosages nor afterwards.
Hematology and coagulation
The following changes could potentially be related to treatment:
- slightly higher reticulocyte percentage in group 3 (1000 mg/kg per day) males on day 30 (3.33% versus 2.13% in control males), mainly due to three animals (Nos. 45, 48 and 49), also noted in one female from this group (No. 51). However, imputability to treatment is doubtful as individual values remained within the range of historical data. Values were back to normal at the end of the 2-week reversibility period.
- slightly higher fibrinogen levels in females from groups 2 (450 mg/kg per day) and 3 (1000 mg/kg per day) on day 34 (1.9 and 1.95 g/L respectively versus 1.62 g/L in control females). A slight increase was still noted at the end of the 2-week reversibility period in two out of four females from group 3 (1000 mg/kg per day). This effect was not observed in males, and could be related to slightly bw values in control females. The following changes, statistically significant when compared with controls, were not considered to be treatment-related:
- slightly lower neutrophil count in males from groups 1 (150 mg/kg per day) and 2 (450 mg/kg per day) resulting in slightly lower white blood cell count in group 1 (150 mg/kg per day) males; this variation was not observed at the high dosage,
- slight]y lower basophil count in males from groups 1 (150 mg/kg per day) and 2 (450 mg/kg per day) on day 30; this variation was not observed at the high dosage,
- slightly higher basophil count in group 3 (1000 mg/kg per day) females on day 50; values were in the same range as control values on day 30.

Blood biochemistry
The following change, observed on day 33, could be attributed to treatment:
- slight decrease in globulin levels resulting in a slight decrease in total protein levels in groups 2 (450 mg/kg per day) and 3 (1000 mg/kg per day) females. These slight modifications were not toxicologically relevant. At the end of the 2-week reversibility period, globulin levels were normal, hut total protein levels were still slightly bw in females. The following variations, statistically significant when compared with controls, were not considered to be related to treatment:
- slight increase in cholesterol levels in males from groups 2 and 3 (450 and 1000 mg/kg per day, respectively); imputability to treatment was not clear since values remained within the range of our historical control values and also because control values were slightly bow, below the range of our historical data (2.27 mmol/L in males).
- slight increase in triglyceride levels in group 3 (1000 mg/kg per day) females, due to slightly bw values in control females on day 33 (lower than the value recorded on day 50);
- very slight increase in GGT levels in males from groups 1, 2 and 3 (150, 450 and 1000 mg/kg per day, respectively) on day 33. This variation has no biological significance. Values were normal at the end of the 2-week reversibility period.
- slight increase in potassium level in group 3 (1000 mg/kg per day) males; values were lower than those recorded for control males on day 50;
- slight decrease in calcium levels in males from groups 1 (150 mg/kg per day) and 2 (450 mg/kg per day) and females from groups 2 (450 mg/kg per day) and 3 (1000 mg/kg per day); individual values remained within the range of our historical data and were similar to those recorded in controls on day 50;
- slight decrease in inorganic phosphorus levels in females from groups 2 (450 mg/kg per day) and 3 (1000 mg/kg per day), due to high control values,
- slight increase in sodium and chloride levels in females from group 3 (1000 mg/kg per day) on day 50, due to slightly lower control values.

Urinalysis
The following change could be related to treatment:
decrease in urinary pH, statistically significant in groups 2 and 3 (450 and 1000 mg/kg per day, respectively) males and without statistical significance in group 3 (1000 mg/kg per day) females.

Necropsy
Organ weights
No treatment-related change was noted.
The statistically significant changes listed below were not considered to be treatment-related:
- slightly higher absolute spleen weight in group 2 (450 mg/kg per day) females on day 34; the relative weight was unchanged,
- slightly higher absolute kidney and thyroid weights in group 3 (1000 mg/kg per day)
males on day 51; no statistically significant change bad been noted on day 34 and relative weights were unchanged on days 34 and 51,
- slightly lower absolute lung weight in group 2 (450 mg/kg per day) males on day 34;
not observed at the high dosage,
- slightly lower relative brain weight in group 3 (1000 mg/kg per day) males on day 51; no statistically significant change bad been noted on day 34;
- slightly lower absolute thymus weight in group 1 (150 mg/kg per day) females on day 34; this change was not observed at the high dosage;

Macroscopy
- Animals euthanized at the end of the treatment period
No treatment-related changes were observed.
- Animal No 58 F (Group 3 - 1000 mg/kg per day) found dead on day 9 This animal, exhibiting a marked curvature of the rachis in the cervical area with prominent epiphysis of the vertebrae, showed signs of poor health status and health deterioration (soiled anogenital area - reduced size of the spleen and thymus attributed to stress-related lymphoid atrophy or involution observed by light microscopy examination) and a red discoloration of the lungs corresponding to a severe
congestion (grade 5) revealed by light microscopy (see below). Gut meteorism noted in this animal was probably due to post-mortem alteration as no related microscopic change was noted.

Light microscopy
All organs and tissues listed in the protocol were examined in end-of-study euthanized animals from groups 0 (control) and 3 (1000 mg/kg/day). In view of the modifications observed and of technical demands, the stomach (non-glandular and glandular), esophagus, duodenum and jejunum were examined in animals from groups 1 (150 mg/kg/day) and 2 (450 mg/kg/day) and for animals from groups 0 (control) and 3 (1000 mg/kg/day) euthanized at the end of the recovery period.
- Animals euthanized at the end of the treatment period the glandular mucosa of the stomach presented the following changes:
- mild (grade 2) hypertrophy of the neck mucous cells
- minimal (grade 1) to moderate (grade 3) basophilia of the upper part of the mucosa
- minimal (grade 1) to moderate (grade 3) hemorrhage infiltration of the upper part of the mucosa
These changes, suggestive of an initiative phenomenon, were observed with a dose-related effect from 150 mg/kg/day upwards. The earliest sign appeared to be an hypertrophy of the neck mucous cells followed by basophilia of the upper part of the epithelium attributed to a mild regenerative process. No degenerative or necrotic cells were observed but only a bw incidence and severity of hemorrhages in the upper part of the mucosa. These changes were completely reversed at the end of the 2-week recovery phase.
Animal No 58 F (Group 3 - 1000 mg/kg per day) found dead on Day 9. This animal, exhibiting a marked curvature of the rachis in the cervical area, showed changes evocative of health deterioration (stress and undenutrition): subcutaneous, mesenteric and perirenal fat tissue atrophy, periportal hepatocyte vacuolation probably steatotic in nature, lymphoid atrophy or involution of the spleen, thymus and mesenteric lymph nodes, acidophilic homogenization and hyperplasia of the adrenocortical cells, atrophy of the pancreatic acini. The mild (grade 2) erosion of the glandular stomach, associated with mild (grade 2) subacute inflammation of the submucosa, might be related to health deterioration (stress-related change). The same is valid for the diestrus phase (reproductive tract at rest). Severe (grade 5) congestion of the lungs and marked (grade 4), mainly centrilobular, congestion of the liver might be agonal in nature and related to a terminal cardiac failure. Although signs indicative of gavage-induced trauma were observed (parietal chronic inflammation areas in the esophagus) and probably due to the rachis curvature making gavage difficult, the cause of health deterioration cannot be ascertained.

Effect levels

Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: irritation of gastric mucosa

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

CONCLUSION

Daily oral administration of SR94653 [(R)-2-chloro mandelic acid] to rats during four weeks at dosages of 0, 150, 450 and 1000 mg/kg per day, followed by a 2-week recovery period at 1000 mg/kg per day induced the following changes:

- mild (at 150 and 450 mg/kg/day) to moderate (at 1000 mg/kg/day) histological changes of the gastric mucosa, suggesting an irritative phenomenon,

- loud breathing, in one male at 450 mg/kg per day at the end of the study (associated with hypothermia) and in three females at 1000 mg/kg per day (transiently in two of them and followed by a deterioration of health and death in the third one); no associated histological findings were seen at necropsy, except for changes suggesting possible misgavage in the female found dead;

- slight hematologic and biochemical changes; however, since variations remained within physiological limits, attribution to treatment cannot be ascertained. No significant toxic effects were noted at the end of the 2-week recovery period.

 

As a conclusion, daily oral administration of SR94653 [(R)-2-chloro mandelic acid] to rats at the dose of 150 mg/kg/day during four weeks only induced mild lesions of the gastric mucosa suggesting a local irritative phenomenon and reversible after cessation of treatment.

Applicant's summary and conclusion

Conclusions:
CL-Freetext:
Daily oral administration of S(R)-2-chloro mandelic acid to
rats at the dose of 150 mg/kg/day during four weeks only induced mild lesions of the gastric mucosa suggesting a local irritative phenomenon and reversible after cessation of treatment .