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Administrative data

Description of key information

A study was conducted to assess the toxic potential of the test substance, when administered to rats by daily oral gavage for a period of 7 consecutive days. It was concluded that the test substance has no toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days up to 1000 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24 January 2008 to 01 February 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study based on OECD Guideline 407 and EU Directive B.7 but dosed for only 7 days rather than the guideline 28 days.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
dosed for 7 days only
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
yes
Remarks:
dosed for 7 days only
Principles of method if other than guideline:
Based on OECD 407 Guideline and EU Directive B.7., but animals were dosed for 7 days rather than 28 days
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: ca. 9 weeks
- Weight at study initiation: Males: 262 - 296 grams; Females: 186 - 204 grams
- Fasting period before study:
- Housing: Group housing of 3 animals per sex in Macrolon cages (MIV type, height 18 cm) with sterilised sawdust as bedding material (Litalabo,
S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lilico & Son (Wonham Mill Ltd), Surrey, U.K.)
- Diet (e.g. ad libitum): Free access (ad libitum) to pelleted rodent diet (SM R/M-Z from SSNIFF, Spezialdiaten GmbH, Soest, Germany).
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3.0°C (actual range 19.9 - 21.5°C)
- Humidity (%): 30 - 70% (actual range 38 - 55%)
- Air changes (per hr): approx. 15/hr
- Photoperiod (hrs dark / hrs light): 12 hrs


IN-LIFE DATES: From: 24 January 2008 To: 01 February 2008
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 4 hours prior to dosing, and were homogenized to visually acceptable levels.


VEHICLE
- Justification for use and choice of vehicle (if other than water): 1% Aqueous carboxymethylcellulose; based on trial formulations performed at
NOTOX and on information from the sponsor
- Concentration in vehicle: 0.0mg/kg/day (controls); 150, 300 & 1000mg/kg/day
- Amount of vehicle (if gavage): 5ml/kg
- Lot/batch no. (if required): Not reported
- Purity: Not reported
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
7 consecutive days
Frequency of treatment:
Once per day
Remarks:
Doses / Concentrations:
150 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
3/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were based on results of the acute oral toxicity study (NOTOXproject 486674) and information from the
sponsor.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: N/A
- Post-exposure recovery period in satellite groups: N/A
- Section schedule rationale (if not random): N/A
Positive control:
N/A
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once/day


BODY WEIGHT: Yes
- Time schedule for examinations: Days 1, 4 & 7


FOOD CONSUMPTION:
- Over Days 1-4 and 4-7



OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Immediately prior to scheduled post-mortem
- Anaesthetic used for blood collection: Yes (identity) iso-flurane
- Animals fasted: Yes
- How many animals: All
- Parameters examined: White blood cells, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Red blood cells, Reticulocytes, red blood cell distribution width, Haemoglobin, Haematocrit, Mean corpuscuiar volume, Mean corpuscular haemoglobin, Mean corpuscular haemoglobin concentration, Platelets, Prothrombin time and Activated Partial thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Immediately prior to scheduled post-mortem
- Animals fasted: Yes
- How many animals: All
- Parameters examined: Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase, Total Protein, Albumin, Total bilirubin, Urea,
Creatinine, Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride, Calcium and Inorganic Phosphate

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes (all animals)
HISTOPATHOLOGY: Yes (groups 1 & 4 plus all gross lesions)
Other examinations:
Organ weights
Statistics:
Means, SD and/or median
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY :
No mortalities occurred during the study and no clinical signs of toxicity were noted during the observation period


BODY WEIGHT AND WEIGHT GAIN
No toxicologically significant changes in body weights and body weight gain were noted.


FOOD CONSUMPTION
No toxicologically significant changes in food consumption before or after allowance for body weight were noted. Food consumption corrected for
body weight of females at 1000 mg/kg/day appeared slightly lower during treatment. Absolute food intake of these animals was essentially similar to control levels. As this change was of a minor nature, this was considered to be of no toxicological relevance.

FOOD EFFICIENCY N/A


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study) N/A


OPHTHALMOSCOPIC EXAMINATION Not conducted


HAEMATOLOGY
Haematological parameters of treated rats were considered not to have been affected by treatment.

CLINICAL CHEMISTRY
Clinical biochemistry parameters of treated rats were considered not to have been affected by treatment.

URINALYSIS Not conducted


NEUROBEHAVIOUR Not conducted


ORGAN WEIGHTS
No toxicologically significant changes were noted in organ weights and organ to body weight ratios.
Liver weights of two males at 1000 mg/kg/day (nos. 10 and 12) appeared slightly higher than control levels. However, these values (and those of
the liver to body weight ratios) were within the range considered normal for rats of this age and strain. Moreover, there were no concurrent
histopathological changes in the liver. Therefore, no toxicological relevance was ascribed to these variations.
GROSS PATHOLOGY
Necropsy did not reveal any toxicologically relevant alterations. Necropsy findings were considered to be of no toxicological significance since they
occurred in the absence of a treatment-related distribution, and are occasionally seen among rats used in these types of studies. These findings
included pelvic dilation of the kidneys, yellowish foci or nodules on the epididymides and fluid in the uterus.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no microscopic findings recorded which could be attributed to treatment with the test substance.

HISTOPATHOLOGY: NEOPLASTIC (if applicable) N/A

HISTORICAL CONTROL DATA (if applicable)
All microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar
incidences and severity in both control and treated rats.


OTHER FINDINGS None
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified

Slight weight loss was observed among female dose groups (see Tables 1 & 2 below), but the incidence of this slight weight loss was unrelated to the dose and was considered to be related to the age of the animals.

Table 1: Body weights (Grams) summary

MALES

 

Treatment

Group 1 (control)

Group 2 (150mg/kg)

Group 3 (300mg/kg)

Group 4 (1000mg/kg)

Day 1

Week 1

MEAN

282

284

284

285

S.D.

13.3

19.3

5.1

10.0

N

3

3

3

3

Day 4

Week 1

MEAN

293

292

292

293

S.D.

13.8

20.6

9.2

15.7

N

3

3

3

3

Day 7

Week 1

MEAN

299

301

296

301

S.D.

17.4

18.9

10.7

19.1

N

3

3

3

3

 

FEMALES

 

Treatment

Group 1 (control)

Group 2 (150mg/kg)

Group 3 (300mg/kg)

Group 4 (1000mg/kg)

Day 1

Week 1

MEAN

194

192

197

197

S.D.

3.6

9.3

8.9

6.5

N

3

3

3

3

Day 4

Week 1

MEAN

191

194

198

196

S.D.

5.5

11.8

10.5

11.6

N

3

3

3

3

Day 7

Week 1

MEAN

197

202

203

198

S.D.

6.4

13.4

10.8

10.5

N

3

3

3

3

S.D: standard deviation

N: number of animals

Table 2: Body weight Gain (%) summary

MALES

 

Treatment

Group 1 (control)

Group 2 (150mg/kg)

Group 3 (300mg/kg)

Group 4 (1000mg/kg)

Day 1

Week 1

MEAN

0

0

0

0

S.D.

0.0

0.0

0.0

0.0

N

3

3

3

3

Day 4

Week 1

MEAN

4

3

3

3

S.D.

0.5

0.7

1.7

1.9

N

3

3

3

3

Day 7

Week 1

MEAN

6

6

4

5

S.D.

1.2

1.7

2.8

3.0

N

3

3

3

3

 

FEMALES

 

Treatment

Group 1 (control)

Group 2 (150mg/kg)

Group 3 (300mg/kg)

Group 4 (1000mg/kg)

Day 1

Week 1

MEAN

0

0

0

0

S.D.

0.0

0.0

0.0

0.0

N

3

3

3

3

Day 4

Week 1

MEAN

-2

1

1

0

S.D.

1.8

1.3

1.7

2.6

N

3

3

3

3

Day 7

Week 1

MEAN

2

5

3

1

S.D.

1.5

2.4

2.8

2.0

N

3

3

3

3

S.D: standard deviation

N: number of animals

Conclusions:
From the results presented in this report it was concluded that Lactol has no toxic potential when administered to rats by daily oral gavage for a
period of up to 7 consecutive days up to 1000 mg/kg/day.
Executive summary:

A study was conducted at NOTOX, The Netherlands, on behalf of Pfizer Ireland Pharmaceuticals Ltd., to assess the toxic potential of the test substance Lactol, when administered to rats by daily oral gavage for a period of 7 consecutive days. The study was conducted to GLP and based on OECD Guideline 407 and EU Directive B.7. However, the animals were dosed for seven days only rather than the 28 days in the guidelines. Lactol was administered by oral gavage to four groups of Wistar rats (each of three rats per sex) at doses of 150, 300 & 1000mg/kg bodyweight/day; a concurrent control group was treated with vehicle only.

Animals were subjected to clinical observations which were undertaken at least once per day and body weights were recorded on days 1, 4 & 7 of the study; food consumption was recorded over days 1-4 and 4-7. Macroscopic examinations were performed and major organs were weighed after terminal sacrifice (Day 7). Immediately prior to post-mortem, blood samples were collected for haematology and clinical biochemistry evaluations. No toxicologically significant changes were noted in any of the parameters investigated in this study (i.e. clinical appearance, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). From the results presented in this report it was concluded that Lactol has no toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days up to 1000 mg/kg/day.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
2 (reliable with restrictions)

Additional information

A study was conducted to assess the toxic potential of the test substance, when administered to rats by daily oral gavage for a period of 7 consecutive days. The study was conducted to GLP and based on OECD 407 and EC B.7. However, the animals were dosed for seven days only. No toxicologically significant changes were noted in any of the parameters investigated in this study (i.e. clinical appearance, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). It was concluded that the test substance has no toxic potential when administered to rats by daily oral gavage for a period of up to 7 consecutive days up to 1000 mg/kg/day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

GLP study based on OECD Guideline 407 and EU Directive B.7 but dosed for only 7 days rather than the guideline 28 days.    

Justification for classification or non-classification

According to the results of the tests and the Official Journal of the European Communities, Annex VI, 'General Classification and Labelling Requirements for Dangerous Substances and Preparations' the substance cannot be classified on the basis of its subacute toxicity as the guidelines stipulate 28 days dose exposure and not the 7 days as in the present study.