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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 05, 2001 till November 16, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to OECD guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents) under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
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)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
440-930-8
EC Name:
-
Cas Number:
330198-48-6
Molecular formula:
C19H28N2O3 / C21H32N2O3 / C23H36N2O3 / C29H50N2O4 / C31H54N2O4 / C33H58N2O4 / C35H62N2O4 / C37H66N2O4
IUPAC Name:
Condensation products of 4-methyl-m-phenylene diisocyanate with alcohols, C10-14 (even numbered)
Details on test material:
Identity: ZP-TIX 1014
Batch number: NW-01-028
Description: solid
Purity: at least 99%
Stable under storage conditions, i.e. at room temperature (17-23°C) in original container away from direct sunlight
Expiry date: 30 Dec 2001
The test item consists of three components.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on animals: Rat, HanBrl: WIST (SPF)
Source of rats: RCC Ltd (Füllingsdorf, Switzerland)
Sex: both
Age of delivery: 6 weeks
Body weight range at acclimatization: males 132-160g (mean 148g)
females 115-136g (mean 123g)
Total number of animals: 20 males and 20 females
Total number of animals per group: 5 males; 5 females (Group 1-4)
Identification: Cage card and individual ear tattoo
Acclimatization: Under test conditions after health examination. Only animal without visible signs of illness were used for the study. Duration: 7 days
Standard Laboratory Conditions
- Air-conditioned with 10-15 air changes per hour
- continously monitored environment with target ranges for temperature 22 +/- 3°C and for relative humidity between 30-70%
- 12 hours flurescent light/12 hours dark (light period 6:00 and 18:00h)
- music during light period
Accommodation: In groups of five per sex in Makrolon type-4 cages with wire mesh tops and standardised softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland)
Diet: Pelleted standard Provimi Kliba 3433 rat maintenance diet ad libitum (batch no. 73/01).
Water: Community tap water from Itingen, Switzerland, ad libitum.
None of the contaminants analyzed in the water and diet is considered to have been present at a concentration which would have affected the validity of the results.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Test item was administrated daily orally via gavage in corn oil (vehicle).
Both sexes (4 groups with 5 rodents each) received the test item at dose levels of:
Group 1: 0mg/kg bw (vehicle control)
Group 2: 15mg/kg bw
Group 3: 50mg/kg bw
Group 4: 150mg/kg bw
Dose volume: 5mL/kg bw

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability (after 2 h and 7 days) of the dose formulations were determined in samples taken after experimental start. Concentration, homogeneity and stability of the dose formulations were determined in samples taken during week 3 of the treatment.
The analyses were performed by RCC Ltd. (Environmental Chemistry & Pharmanalytics Division) according to a HPLC method supplied by the Sponsor.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0mg/kg bw (vehicle control)
Basis:
other: in corn oil related to body weight
Remarks:
Doses / Concentrations:
15mg/kg bw
Basis:
other: in corn oil related to body weight
Remarks:
Doses / Concentrations:
50mg/kg bw
Basis:
other: in corn oil related to body weight
Remarks:
Doses / Concentrations:
150mg/kg bw
Basis:
other: in corn oil related to body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
ZP-TIX 1014 in corn oil was administered daily by oral gavage to SPF bred Wistar rats of both sexes at dose levels of 15, 50 and 150mg/kg bw/day for a period of 28 days. A control group was treated similary with the vehicle, corn oil, only.
Positive control:
no

Examinations

Observations and examinations performed and frequency:

mortality/viability:
- recording twice daily

general cageside observation (clinical signs):
- recorded once before commencement of administration
- twice daily on days 1-3
- once daily on days 4-28

detailed clinical observation:
- performed in random sequence
- once before commencement of administration
- once weekly (weeks 1-3)

food consumption:
- recorded once during the pretest period
- weekly thereafter

body weights:
- recorded weekly during pretest
- weekly during treatment
- before necropsy

functional observational battery:
- recorded during week 4
- modified Irwin screen test
- grip strength
- locomotor activity

clinical laboratory investigations:
- performed after week 4
- blood sampling in light isoflurane anesthesia via retro-orbital plexus (18h fasted before)
- standard hematology and clinical biochemistry parameter were checked (see table below)

hematology parameter:
- erythrocyte count
- hemoglobin
- hematocrit
- mean corpuscular volume
- mean corpuscular haemoglobin
- mean corpuscular haemoglobin concentration
- platelet count
- reticulocyte count
- reticulocyte fluorescence ratios
- nucleated erythrocytes (normoblasts)
- heinz bodies
- methemoglobin
- total leukocyte count
- differential leukocyte count
- red blood cell morphology
- thromboplastin time (=prothrombin time)
-activated partial thromboplastin time

clincal biochemistry parameter:
- Glucose
- Urea
- Creatinine
- Uric Acid
- Bilirubin, total
- Cholesterol, total
- Triglycerides
- Phospholipids
- Aspartate aminotransferase
- Alanine aminotransferase
- Lactate dehydrogenase
- Creatine kinase
- Alkaline phosphatase
- Gamma-glutamyl transferase
- Calcium
- Phosphorus
- Sodium
- Potassium
- Chloride
- Albumin
- Protein, total
- Globulin
- Albumin/Globulin ratio

Sacrifice and pathology:
Sacrifice:
All animals were anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination.

Gross Pathology:
- description of all macroskopic abnormalities were recorded
- organs were weight (see table below)

Weighed organs:
- Brain
- Heart
- Liver
- Thymus
- Kidneys
- Adrenals
- Spleen
- Testes
- Epididymides
- Ovaries

Histopathology:
- samples of tissues and organs were collected from all animals at necropsy.
- samples were fixed in neutral phosphate buffered 4% formaldehyde solution.
- standard histopathological sampling was done (see table below for tissues and organs sampled).
- * marked organs or tissue samples from control and high-dose group were examined by a pathologist.

Tissues and organs sampled:
- Adrenal glands*
- Aorta
- Bone (sternum, femur including joint)
- Bone marrow (femur)*
- Brain (cerebrum, cerebellum, brain stem)*
- Cecum*
- Colon*
- Duodenum*
- Epididymides (fixed in Bouin's solution)*
- Esophagus
- Eyes with optic nerve (fixed in Davidson's solution)
- Harderian gland (fixed in Davidson's solution)
- Heart*
- Ileum, with Peyer's patches*
- Jejunum with Peyer's patches*
- Kidneys*
- Larynx
- Lacrimal gland, exorbital
- Liver*
- Lungs, filled w/formalin at necropsy*
- Lymph nodes - mesenteric, mandibular*
- Mammary gland area
- Nasal cavity
- Ovaries*
- Pancreas
- Pituitary gland
- Prostate gland*
- Rectum*
- Salivary glands - mandibular, sublingual
- Sciatic nerve*
- Seminal vesicles*
- Skeletal muscle
- Skin
- Spinal cord. cervical, midthoracic, lumbar*
- Spleen*
- Stomach*
- Testes (fixed In Bouin's solution)*
- Thymus*
- Thyroid (incl. parathyroid gland, if possible)*
- Tongue
- Trachea*
- Urinary bladder, filled w/formalin at necropsy*
- Uterus*
- Vagina*
- Gross lesions*

- All organs and tissue samples were processed, embedded and cut to 2 to 4 micrometers and stained with hematoxylin and eosin.


Statistics:
The following statistical methods were used to analyze the body weight, organ weights and ratios, as well as clinical laboratory data:
- Dunnett-test (many to one t-test)
- Steel-test (many-one rank test) was applied instead of Dunnett-test when data could not be assumed to follow a normal distribution.
- Student´s t-test was applied to grip strength and locomotor activitiy.
- Fisher´s exact-test was applied to the macroscopic findings.

Results and discussion

Results of examinations

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:
no effects observed
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):
no effects observed
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:
no effects observed
Details on results:
Viability/Mortality:
- All Animals survived the scheduled study period.

Body weight:
- The body weight and the mean body weight gain of the test item-treated animals were similar to those of the control group.

Food consumption:
- No test item related differences in food consumption and relative food consumption were evident when compared with the controls.

Hematology:
- Leukocyte and lymphocyte count was significantly increased in the males treated with 150mg/kg bw. This effect was considered to be not test item related because no increase of this parameter was measured in females.
- Thromboplastin time was significant increased in males and females treated with 50mg/kg bw and in males treated with 150mg/kg bw. These increased values in males and females remained within the range of historical control data and due to the lack of effect in the female high dose group, this effect was not increase dose dependent.
- No further significant changes of hematological parameter were measured.

Clincal biochemistry:
- Total bilirubin was significantly decreased in males treated with 50mg/kg bw. This was considered to be incidental because this decrease was not dose dependent and no significant decrease could be seen in females.
- The aspartate aminotransferase activity was significantly increased in males and females treated with 50 mg/kg/day and in females treated with 150 mg/kg/day. This effect was considered to be unrelated to the test item because no dose dependence could be seen. The value lies within the range of the historical data and the control value of females was slightly lower than the historical control.
- The total cholesterol , the triglycerides, phospholipides were significantly increased in males treated with 50 or 150 mg/kg/day. The increase of all three parameters was not dose dependent and could not be observed in females.
- The alkaline phosphatase was significantly increased in males treated with 50 mg/kg/day or 150 mg/kg/day. This effect was not dose dependent and not seen in females.
- The y-glutamyltransferase activity was significantly inereased in males treated with 150 mg/kg/day. This effect was considered to be incidentally because no dose dependence eould be seen. The value lies within the range of the historical data and low control values were measured in males and females compared with historical control data.
- The globulin was significantly increased and consequently the albumin to globulin ratio was decreased in males treated with 15 mg/kg/day. This effect was not dose dependent and therefore considered to be incidental.
- A significantly increased value of phosphorus was measured in females treated with 150 mg/kg/ day of the test item. This effect was not considered to be test item related because it was not seen in males and due to comparable low values in the controls.
- All remaining clinical biochemistry parameters were considered to be unaffected by the treatment with the test item.

General cageside observations (daily):
- Slightly pale feces was observed in animals of both sexes in controls and animals treated with 15 mg/kg/day from study day eleven, in animals treated with 50 mg/kg/day from day eight. This was considered to be due to administration of the vehicle.
- Slightly yellowish feces was observed in all animals treated with 150 mg/kg/day from study day eight until the end of the study. This was due to a passive effect of the test item rather than an indication of systemic toxicity.

Detailed clinical observation (weekly):
- No clinical signs were observed during weeks 1 to 3

Neurobehavior (functional obervational battery):
- Grip Strength:
The fore- and hindlimb grip strength of test item-treated females was similar to those ot control females. Slightly decreased hindlimb grip strength was found in males treated with 15 mg/kg/day of the test item. Slightly to moderately increased forelimb grip strength were observed in males trea ted with 50 mg/kg/day or 150 mg/kg/day of the test item. These contrary findings were not considered to be test item related.
- Locomotor activity:
The mean locomotor activity recorded over 60 minutes in males of all test item-treated groups was similar to that of the control group.
The mean locomotor activity recorded trom 0 to 15 minutes was significantly increased in females treated with 50 mg/kg/day of the test item. This effect was not dose dependent and reversible within the observation period. Therefore the increase was considered to be not test item related. Furthermore low values were observed in the contro! females when compared with the historical control values.

Gross pathology:
- Organ weights:
No test item-related differences in organ weights were noted when compared with the controls. A small number of statistically significant differences were noted in some animals treated with 15 or 50 mg/kg/day when compared with the controls. In the absence of clear dose-response relationship, all were considered to be incidental changes.
- Macroscopic findings:
A number of maeroscopic findings were observed in control rats and rats treated with 150 mg/kg/day. No findings were observed that were considered to be related to the administration of the test item at the end of the 28-day treatment period. All findings diagnosed either did not distinguish treated rats from controls or were considered to be of no toxicological relevance.
- Microscopic findings:
A number of microscopic findings were observed in control rats and rats treated with 150 mg/kg/day atter the 28-day treatment period. The incidence and severity of these histopathologie findings either did not distinguish treated rats from controls or were considered to be of no toxicological significance.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
<= 150 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
>= 150 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral administration of ZP-TIX 1014 to Wistar rats at doses of 15, 50 and 150 mg/kg bw/day, for 28 days resulted in no effects upon major toxicological parameters.
Based on the results of this study, 150mg/kg body weight/day of ZP-TIX 1014 was established as the no-observed-effect-level (NOEL) and no-observed-adverse-effect-level (NOAEL).
Executive summary:
General:

In this subacute toxicity study, ZP-TIX 1014 was administered daily by oral gavage to SPF¬bred Wistar rats of both sexes at dose levels of 15, 50 and 150 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, corn oil, only.

The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment.

 

Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest and the treatment period. Functional observational battery, locomotor activity and grip strength were performed during week 4.

 

At the end of the dosing period, blood samples were withdrawn for hematology and plasma chemistry analyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals.

 

The study was conducted according to OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents).

 

Mortality/Viability:

All animals survived the scheduled study period.

 

Clinical signs:

No test item-related clinical signs of toxicological relevance were noted during daily or weekly observations (pretest to week 3).

 

Functional observation battery:

No test item-related findings of toxicological relevance were seen during functional

observation battery (week 4).

-        Grip strength

No test item-related changes in fore- or hind-limb grip strength were observed

-        Locomotor Activity

No test item-related differences toxicological relevance in mean locomotor activity were noted.

 

Body weight:

The mean body weights and the mean body weight gain compared well with those of the controls.

 

Food consumption:

The mean daily and relative food consumption of the test item treated animals compared well to those of the control animals.

 

Clinical laboratory investigations:

-        Hematology

No test item-related changes in the hematology parameters were observed.

-        Clinical biochemistry

No test item-related differences in parameters of clinical biochemistry were evident.

 

Gross pathology / Histophathology:

-        Organ weights

No test item-related changes in absolute or relative organ weights were observed when compared with controls.

-        Macroscopic / Microscopic findings

A number of macroscopic findings were recorded. These findings did not distinguish treated rats from controls.

A number of microscopic findings were noted in the organs and tissues examined. The type, incidence and severity of these findings did not distinguish treated rats from controls.