Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
An acute toxicity study is not necessary as there is data available from short-term 14-day repeated dose toxicity studies of CD08467 and CD08479 in minipigs and rats, respectively. Repeated dose-administration studies supersede the need of additional single dose acute toxicity testing.

The acute toxicity potential of CD08467 as well as its analogue CD08479 has been investigated in a few short-term duration studies (see IUCLID section 7.5.1: Weiler, 2012 and Maury, 2012). CD08467 was administered daily for 2 weeks via oral gavage to Göttingen® minipigs at 300, 600, or 1 200 mg/kg bw/day (the maximal feasible dose due to the limit of formulability of CD08467). No mortality was observed with all 3 doses and slight treatment-related effects were seen only at the highest dose of 1 200 mg/kg. No toxicity was seen at 300 or 600 mg/kg bw/day. In another study, CD08479, the structurally related analogue of CD08467, was administered daily to rats at 420 mg/kg bw/day for 2 weeks, and no toxicity was observed at this dose. Thus, the acute non-toxic dose levels have been demonstrated to be 600 mg/kg bw/day in minipigs for CD08467 and 420 mg/kg bw/day in rats for CD08479.
Based on the available data showing no mortality of both studies, it can be expected that the LD50 of CD08467 by oral route is higher than the maximal feasible dose of 1 200 mg/kg bw/day in the minipigs (non-rodent toxicity with CD08467) or higher than 420 mg/kg bw/day in the rat (rodent toxicity with CD08479).

In addition, both CD08467 and CD08479 are rapidly converted into salicylic acid and benzoic acid (1 mol CD08467 or CD08479 yields 1 mol salicylic acid and 1 mol benzoic acid), which are known compounds with available acute toxicity data. According to the ECHA’s C&L inventory, benzoic acid is not classified for acute toxicity, but salicylic acid is classified as Acute Tox. 4 (H302) based on a LD50 of 891 mg/kg bw (see registration dossier of salicylic acid). By extrapolating the LD50 of salicylic acid (MW = 122.12 g/mol) to CD08467 (MW = 344.32 g/mol), the LD50 for CD08467 would be 2512 mg/kg bw, and thus, no classification is warranted for CD08467 for acute toxicity based on the criteria under CLP Regulation.

For further details see attached justification “CD08467 Acute toxicity waiver 7844907273609635930.pdf”
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2012-01-30 to 2012-08-13
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: The objectives of this study were the following: [1] to assess the potential systemic toxicity of CD08467 formulated in vehicle (CMC 0.1% PG 4%/0.2 % Poloxamer 124) in male and female Göttingen® minipigs upon repeated daily oral administration (gavage) at 300, 600 or 1200 mg/kg/day for at least two consecutive weeks and [2] to determine the concentrations of CD08467 main metabolites, CD0345 (salicylic acid) ,and CD08465 (carbonate moiety) in plasma samples (Proof of exposure) from male and female Göttingen® minipigs after multiple oral administration for approximately two consecutive weeks.

- Short description of test conditions: In each group one male and one female naïve Göttingen® minipigs received single daily oral doses of CD08467 at 300, 600 or 1200 mg/kg/day for two weeks at the dosing volume of 10 mL/kg/day.

- Parameters analysed / observed: Parameters evaluated included mortality/morbidity, clinical observations (at least twice a day), bodyweight and food consumption (once a week). After a 14-day treatment period, blood samples were collected at 0.5, 1, 4 and 8 hours after treatment for determination of plasma drug levels. Plasma CD08465 and CD0345 concentrations were analysed in collected samples using a HPLC method with TIS-MS/MS detection (Limit of Quantification: 0.5 ng/mL and 150 ng/mL for CD08465 and CD0345, respectively). At the end of the dosing period, all animals were subjected to necropsy procedure. Selected organs and tissues were sampled and weighed, and histopathological evaluation was performed.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
- Name: CD08467
- Appearance: Off-White Powder
- Purity: 98.3%LC

SOURCE OF TEST MATERIAL
- Source and lot/batch No. of test material: Source: Unité de Gestion de la Librairie Chimique (UGLC); Batch No.: 11.00664
- Expiration date of the lot/batch: 2012-02-29

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Stability of the test item in vehicle between 1 mg/mL and 100 mg/mL at ambient temperature, under magnetic agitation and protected from light was demonstrated stable at 1 mg/mL and 100 mg/mL during ten days. The dosage form preparation was manufactured six times and delivered as ready-to-use formulations.
- Storage conditions: During the study, the dosage form preparations were stored in the study room dedicated to test items storage (Room # C.1.3.10), according to the instruction from the supplying department. Except during dispatching, the dosage form preparations were kept under continuous agitation (magnetic stirrer) during the preparation, storage and dosing procedures.
Species:
pig
Strain:
other: Göttingen® minipigs
Details on species / strain selection:
The Göttingen® minipig was selected as test system because it is a non-rodent species commonly used for conducting research in pharmacology and toxicology; hence, sufficient background data exist to support interpretation of results.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animals were delivered from Ellegaard, Dalmose, Denmark.
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 3 to 4 months
- Weight at study initiation: 6.7 to 7.5 kg for both males and females
- Housing: Animals were housed in a conventional “minipig unit” with restricted entry in pens containing wood shavings (FB8/10, Anibed, Pontvallain, France) for bedding material. Each 2 m2 pen contained one minipig.
- Diet: The feeding rations of pelleted complete diet (SDS, Saint Gratien, France) were calculated as specified by the breeder (Ellegaard) according to the animal’s age. The rations were given twice a day as equal amounts; animals had access to their first daily ration approximately 1 hour after dosing. The feeding ration was adjusted according to the oldest animal included in the study.
- Water: ad libitum, tap water
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C ± 3 °C
- Humidity (%): 50 ± 20%
- Air changes (per hr): 15 to 20
- Photoperiod (hrs dark / hrs light): 12/12

OTHER: Before their arrival, the animals were subjected to a biological follow-up against the principal diseases found in the (mini)pig species, following the FELASA recommendations (viral – bacterial – fungal and parasitological infections). Upon their arrival at Galderma R&D, each animal was given a complete clinical examination including the general appearance (posture, behaviour, head, teguments, anogenital region, tail etc.) and a palpation of the abdominal region under the supervision of a veterinarian. In addition, the animals were treated against parasitic arthropods and helminths using an appropriate prophylactic treatment (Ivermectine).
Route of administration:
oral: gavage
Details on route of administration:
Animals were treated orally by gavage using a plastic syringe fitted with an esophageal cannula. Immediately after dosing, tap water was used for flushing the cannula (approximately 5 mL, equivalent to the cannula dead volume) in order to administer entirely the test item.
Vehicle:
other:
Remarks:
Carboxymethyl cellulose (CMC) 0.1% / PG 4% / 0.2% Poloxamer 124
Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: CD08467 was supplied as weighed raw material (Drug Substance). The drug substance was reconstituted in vehicle to obtain final dosage forms at required concentrations (30, 60 and 120 mg/mL) by the supplying department (UGLC).

- VEHICLE
- Justification for use and choice of vehicle (if other than water): CD08467 formulated in vehicle containing carboxymethyl cellulose (CMC) 0.1% / PG 4% / 0.2% Poloxamer 124 was demonstrated to be stable at 1 and 100 mg/mL.
- Concentration in vehicle:
- Purity: CMC 0.1% / PG 4% / 0.2% Poloxamer 124
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity (2 samples) and concentrations were checked before the beginning of the study with a range of acceptability of 85-115%. These checks were conducted twice (first and second preparations) out of six.
Duration of treatment / exposure:
at least 2 consecutive weeks
Frequency of treatment:
once daily, at approximately the same time each day, 7 days a week
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
Dose / conc.:
1 200 mg/kg bw/day (nominal)
No. of animals per sex per dose:
1
Control animals:
yes, concurrent vehicle
Positive control:
Not applicable
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily during both pre-dosing and dosing periods (including during non-working days) for mortality or signs of morbidity.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were regularly observed at least once daily during both pre-dosing and dosing period (after treatment) to detect any behavioural and physical abnormalities. The nature, onset, severity and duration of clinical signs were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights of each animal were recorded weekly during the pre-dosing period, on Day -1, once a week during the dosing period and prior to necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
The amount of food consumed by each animal was estimated by noting the difference between the quantities given per day (twice daily) and that remaining before the following ration distribution. This was performed daily during both pre-dosing and dosing periods. Food consumption was expressed as a percentage of the quantity given. Whenever fasting was required, the food was removed at the end of the day and the estimation of food consumed was made at that time.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: Not specified

HAEMATOLOGY: Not specified

CLINICAL CHEMISTRY: Not specified

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

IMMUNOLOGY: Not specified

OTHER: Determination of plasma drug levels
Time schedule: Blood samples were taken from all animals at the following time points: 0.5 h, 1 h, 4 h, and 8 h post-dosing (four time points per animal). Animals were fasted overnight (maximum 20 hours) before the blood sampling procedure for
clinical pathology investigations, any anaesthesia procedure (skin biopsy) and before the final sacrifice.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see Table 1 in box "Any other information on materials & methods incl. tables")

HISTOPATHOLOGY: Yes (see Table 1 in box "Any other information on materials & methods incl. tables")
Other examinations:
Organ weights: At scheduled necropsy, selected organs, as listed in the Table 1 in "Any other information on materials & methods incl. tables" section, were weighed (fresh). Paired organs were weighed together (except if a difference in size was observed macroscopically). Organ weights were expressed as absolute values (g) and relative values (g per 1000 g of body weight).
Statistics:
Owing to the small sample size (n = 1 per group per sex), no statistical analysis could be performed. An animal-by-animal analysis was done and data from treated animals were compared with control animal data.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No clinical signs were observed during the two weeks of treatment with CD08467 except vomiting in the high dose group.
The female (8F) vomited on Day 4 and on Day 14 (about 10 minutes after treatment) as well as male (7M) on Day 14.
A relationship with the high dose level administered cannot be ruled out.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Compared to control values, there were notable changes in the body weight for female from high dose group and in the body weight gain for both sexes from high dose group. This effect is considered linked with the high dose of CD08467 administered. In both male and female, when compared to body weight gain in control, decrease in body weight gain (-62.5% and -137%, respectively) was observed at the high dose of 1200 mg/kg/day. This effect was particularly marked during the second week of treatment. Consequently, this dose was considered to exceed the maximum tolerated dose. By contrast, no clear effect was observed at the 300 and the 600 mg/kg/day in male and female.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 1200 mg/kg/day, there was a reduction in food consumption during the second week of the study in the female and from Day 13 for the male. In the high-dose group, the male ate 75% of the given feeding ration on Day 13 (AM), 25% on Day 13 (PM) and 25% on Day 14 (AM). This male did not eat on the Day 14 (PM). Female did not eat her entire feeding ration during the 2nd week of the study in the high-dose group.

Males and females of the control and other dose groups ate their entire feeding rations (i.e. 100%).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
The female animal at the high-dose group showed a high liver weight (absolute and relative) when compared to the other females. This was correlated with the pale appearance noted at necropsy and the diffuse hepatocytes vacuolation observed at microscopic examination. Other individual variations were observed with no dose-effect relationship trend or microscopic correlation. Considering the low number of animals in the study, no consistent trend could be identified on organ weight changes.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
With the female animal at the high-dose group, a pale appearance of the liver was observed in correlation with a higher liver weight and with the microscopic findings (hepatocytes vacuolation). Other macroscopic findings in the same animal were observed including: dark abnormal colour in the cardia region of the stomach (correlated with the presence of multifocal ulcers / erosions), brown deposits at the surface of the tongue (in correlation with diffuse erosion with bacterial clusters). In addition, a diffuse dark red abnormal colour was noted in the abdominal cavity (no sample done). A possible relationship with the gavage procedure and/or with the administration of CD08467 cannot be excluded.

A dark abnormal colour was observed in the thoracic cavity of several animals including the control animals (male and female in group 1 (control), female in group 3, male and female in group 4). This finding was associated in some animals with a dark abnormal colour of the thymus, which was correlated with the presence of hemorrhagic tissue surrounding the thymus. Considering the absence of dose-effect relationship and the anatomical location, these findings were considered to be related to the blood sampling procedure. The few other macroscopic findings observed in this study did not show dose-effect relationship and were considered to be part of the normal background of minipigs of this age and strain.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The female animal at the high-dose group showed microscopic findings in several organs/tissues:
- Slight but diffuse hepatocytes vacuolation of the liver. This finding was correlated with the pale appearance and a higher liver weight.
- Moderate 'starry sky' pattern in the thymus.
- Multifocal ulcers/ erosions in the cardia region of the stomach and diffuse erosion with bacterial clusters at the surface of the tongue in correlation with the macroscopic observations.

The few other microscopic findings observed in this study were considered to be part of the normal background of minipigs of this age and this strain.
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Plasma concentrations: All treated animals had detectable levels of both key metabolites of CD08467 (i.e. CD08465 and CD0345) at all time points measured. Concentrations of both metabolites increased with the dose. There were no differences between the sexes. CD0345 was by far the predominant metabolite with maximum values of 189,954 ng/mL, 296,830 ng/mL and 609,370 ng/mL at 8 h found in the males treated with 300, 600 and 1200 mg/kg/day, respectively, and 148,973 ng/mL at 4 h, 254,781 ng /mL at 8 h, 853,005 ng/mL at 4 h in females treated with 300, 600 or 1200 mg/kg/day, respectively.
Details on results:
The systemic exposure to CD08467 metabolites (CD0345 and CD08465) was demonstrated in all treated animals. CD0345 (salicylic acid) was the predominant metabolite with maximum values of 609,370 ng/mL in males and 853,005 ng/mL in females treated with 1200 mg/kg/day. No treatment-related mortality occurred during the study and there were no notable treatment-related effects at 300 and 600 mg/kg/day.

At 1200 mg/kg/day notable effects on physiological parameters, such as reduced body weight and food consumption were noticed. These signs were associated with microscopic findings in the female of high dose level group such as multifocal ulcers/ erosions in the cardia region of the stomach and slight but diffuse hepatocytes vacuolation of the liver. These microscopic findings associated with effects on physiological parameters could be related to the high dose level.
Remarks on result:
not determinable because of methodological limitations
Critical effects observed:
not specified
Conclusions:
The oral administration of CD08467 at 300 and 600 mg/kg/day to male and female Göttingen® minipigs for fourteen consecutives days was well tolerated and not associated with any toxicological findings. At the high dose level of 1200 mg/kg/day, slight treatment-related effects were observed on physiological parameters such as body weight loss, decreased food consumption and few slight microscopic findings in the liver and stomach. No NOAEL could be determined due to methodological limitations (only 1 animal per sex per dose used; non-GLP).
Executive summary:

In a 14-day repeated dose toxicity study, the test item CD08467 (purity: 98.3%LC) was applied orally by gavage to Göttingen® minipigs (1/sex/dose) at dose levels of 0, 300, 600 and 1200 mg/kg bw/day for 14 days. Animals were observed for mortality/morbidity, clinical observations (at least twice a day), body weight and food consumption. After 14 days, blood samples were collected for determination of plasma drug levels. Plasma CD08465 and CD0345 concentrations were analysed, and at the end of the dosing period, all animals were subjected to necropsy procedure. Selected organs and tissues were sampled and weighed, and histopathological evaluation was performed.

At 1200 mg/kg/day, notable effects on physiological parameters, such as reduced body weight and food consumption, were noticed. These signs were associated with microscopic findings in the female of high dose level group such as multifocal ulcers/erosions in the cardia region of the stomach and slight but diffuse hepatocytes vacuolation of the liver. These microscopic findings associated with effects on physiological parameters could be related to the high dose level.

However, no NOAEL could be determined due to methodological limitations (only 1 animal per dose used; non-GLP).

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
For justification of read-across please refer to the read-across statement in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Few crusts/wounds were observed, some due to transponder implantation. Hairloss was observed in one female and was considered to be part of the background changes. Additionally, exophthalmia was observed in one female after blood sampling removal from the retro-orbital venous plexus. Such clinical signs were not considered treatment-related.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
A slight tendency to body weight decrease was observed in males exposed to 260 mg/kg bw/day and 420 mg/kg bw/day of CD08479 without reaching a statistical significance (see Table 2 in box "Any other information on results incl. tables").
A non-statistically significant lower mean body weight gain was observed in males exposed to 260 mg/kg bw/day and 420 mg/kg bw/day of CD08479 at the end of the dosing period (approximately – 17.38% and -26.5%, respectively; see Table 3 in box "Any other information on results incl. tables").
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
A slight dose-related decrease of thymus weight was observed in males exposed to 260 mg/kg bw/day and 420 mg/kg bw/day of CD08479. A tendency to decrease was also observed in females exposed to 420 mg/kg bw/day of CD0847 but did not reach statistical significance: -21% in absolute weight and -17% in relative weight. Most individual absolute values in these groups were below the first quartile of the historical control data (both sexes) or even outside of the historical ranges (females). Despite the absence of associated microscopic change, this finding was considered to be possibly related to CD08479 exposure (See Table 4 in box "Any other information on results incl. tables").

Changes not considered to be related to the administration of CD08479:
In females only, the kidneys absolute and relative weight was slightly higher in all treated group, this difference reaching statistical significance at 260 mg/kg/day and 420 mg/kg/day. However, the control means were low mainly due to one female and, thus, this difference was not considered of biological significance.
The liver absolute and relative weight of males and females treated with CD08479 at 420 mg/kg/day were slightly higher than in controls. Although reaching statistical significance for the relative weight, this difference was mainly related to one animal in each sex exposed to 420 mg/kg/day and was not associated with microscopic findings. Therefore, this finding was not considered of toxicological significance.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Plasma concentrations: All treated animals had detectable levels of both key metabolites of CD08469 (i.e. CD08465 and CD0345) at all time points measured. Concentrations of both metabolites increased with the dose. There were no differences between the sexes. CD0345 was by far the predominant metabolite with maximum values of 112700 ng/mL, 260933 ng/mL and 362067 ng/mL at 8 h found in the males treated with 90, 260 or 420 mg/kg bw/day, respectively, and 116633 ng/mL, 268500 ng /mL, 356450 ng/mL at 8 h in females treated with 90, 260 or 420 mg/kg bw/day, respectively.
Details on results:
The systemic exposure to CD08479 metabolites (CD0345 and CD08465) was demonstrated in all treated animals. CD0345 (salicylic acid) was the predominant metabolite with maximum values of 362067 ng/mL in males and 356450 ng/mL in females treated with 420 mg/kg bw/day. No treatment-related mortality occurred during the study and there were no notable treatment-related effects at 90 and 260 mg/kg bw/day. A slight tendency to decrease was observed in males body weight and body weight gain at 260 and 420 mg/kg/day without reaching statistical significance. As these differences were mainly related to one animal in each group showing lower body weight, this finding was not considered to have any toxicological significance. Moreover, at necropsy only a slight tendency to terminal body weight decrease was also observed in both males and females reaching respectively -4.9 % and -0.25% at 420 mg/kg/day but without statistical significance, and only a slight decrease of thymus weight was observed in males at the same doses without histopathological correlation. Despite the absence of associated microscopic change, this finding was considered to be possibly related to the administration of CD08479. In the absence of any notable effect on other physiological parameters, it was not considered to be adverse.
Key result
Dose descriptor:
NOAEL
Effect level:
420 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect observed at highest dose level
Critical effects observed:
not specified

Table 2: Body weight

Groups 1
(Control)
2
(CD08479
90 mg/kg bw/day)
3
(CD08479
260 mg/kg bw/day)
4
(CD08479
420 mg/kg bw/day)
Daily volume (mL/kg/day 10 10 10 10
Number of animals M:6 F:6 M:6 F:6 M:6 F:6 M:6 F:6
Body weight, g (%) (a) 313.0 196.03 -1.50 2.04 -3.19 -1.27 -4.88 -0.25

(a) At end of dosing period. For absolute controls, group means are shown. For treated groups, percent differences from absolute controls are shown. Statistical analysis, based on actual data (not on the percent differences), did not indicate any statistically significant differences.

Table 3: Body weight gain

Groups 1
(Control)
2
(CD08479
90 mg/kg bw/day)
3
(CD08479
260 mg/kg bw/day)
4
(CD08479
420 mg/kg bw/day)
Daily volume (mL/kg/day 10 10 10 10
Number of animals M:6 F:6 M:6 F:6 M:6 F:6 M:6 F:6
Body weight gain, g (%) (a) 53.5 15.8 -6.2 34.18 -17.38 -6.33 -26.5 7.59

(a) At end of dosing period. For absolute controls, group means are shown. For treated groups, percent differences from absolute controls are shown. Statistical analysis, based on actual data (not on the percent differences), did not indicate any statistically significant differences.

Table 4: Thymus weight changes

Groups 1
(Control)
2
(CD08479
90 mg/kg bw/day)
3
(CD08479
260 mg/kg bw/day)
4
(CD08479
420 mg/kg bw/day)
  M F M F M F M F
Absolute weight, g (%) (a) 0.53695 0.40577 +2 +25 -21* +1 -25 * -21
Relative weight weight, g (%) (a) 1.9 2.2 +4 +23 -18 +4 -22 -17

(a) For controls, group means are shown. For treated groups, percent differences from vehicle controls are shown.*: p<0.05.

Conclusions:
The oral administration of CD08479 at 90 mg/kg bw/day to male and at 90, 260 and 420 mg/kg bw/day to female Wistar rats for fourteen consecutives days was well tolerated and not associated with any toxicological findings. At the highest dose levels of 260 and 420 mg/kg bw/day, slight treatment-related effects was observed in males on physiological parameters such as body weight loss without reaching statistical significance. At necropsy only a slight decrease of thymus weight was observed in males at the same doses (260 and 420 mg/kg bw/day) without histopathological correlation. Therefore, a no-observed-adverse effect level (NOAEL) of 420 mg/kg bw/day was estasblished since thymus changes were not considered to be adverse regarding their low magnitude and the absence of any associated microscopic findings.
Executive summary:

In a 14-day repeated dose toxicity study, the test item CD08479 (purity: 98.1%) was applied orally by gavage to Wistar rats (6/sex/dose) at dose levels of 0, 90, 260 or 420 mg/kg bw/day in carboxymethyl cellulose (CMC) 0.1% / PG 4% / 0.2% Poloxamer 124 for 14 consecutive days. Animals were observed for mortality/morbidity, clinical observations (at least once a day), body weight and food consumption. After 14 days, blood samples were collected for determination of plasma drug levels. Plasma CD08465 and CD0345 concentrations were analysed, and at the end of the dosing period, all animals were subjected to necropsy procedure. Selected organs and tissues were sampled and weighed, and histopathological evaluation was performed.

At 260 and 420 mg/kg bw/day in male Wistar rats, slight effects on physiological parameters, such as reduced body weight were noticed without reaching statistical significance. As these differences were mainly related to one animal in each group showing lower body weight, this finding was not considered to have any toxicological significance. Moreover, at necropsy slight decrease in thymus weight in males was observed at 260 and 420 mg/kg bw/day. However, these changes were not considered to be adverse regarding their low magnitude and the absence of any associated microscopic findings.

Therefore, a NOAEL of 420 mg/kg bw/day for both sexes could be determined since thymus changes in males were not considered to be adverse.

This information is used in a read-across approach in the assessment of the target substance. 

For justification of read-across please refer to the attached read-across statement (see IUCLID section 13).

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion