Tetra-n-butyl titanate, polymer with water

Repeated dose toxicity: oral

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Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

August 19, 1985 to November 26, 1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

The study was conducted in accordance with standard operating procedure of Toxicity Research Laboratory (TRL) with Compliance of GLP but do not specify guideline followed.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Four groups of male and female Sprague-Dawley rats (30/sex/group) were administered daily 0, 30, 125 or 500 mg/kg bw/day for either 6 or 13 weeks.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Constituent 2

Reference substance name:

Butan-1-ol

EC Number:

200-751-6

EC Name:

Butan-1-ol

Cas Number:

71-36-3

Molecular formula:

C4H10O

IUPAC Name:

1-Butanol

Test material form:

other: liquid

Details on test material:

- Name of test material: n-Butanol:
- Physical state: liquid
- Analytical purity: 99.9%
- Purity test date: feb 12, 1985
- Lot/batch No.: 3597 KVVE

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charls River Breeding laboratory, Inc., Portage, Michigan
- Age at study initiation: 22-23 days
- Weight at study initiation: 45-55 gram
- Diet (e.g. ad libitum): Purina certified Rodent laboratory chow #5002 (pellet)
- Water (e.g. ad libitum): Filtered municple water, analyzer periodically for the presence of contaminants as defined by EPA.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70.2 ± 2.2
- Humidity (%): 47.6±9.2
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: August 12, 1985 To: november 25 and 26, 1985

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Test substance analysis was done by Gas chromatography -Hewlett Packard 5880 with automated sampler and varian flame ionization detector is used with following standard set
Injector Temperature : 150 ̊C
column Temperature : 140 ̊C isothermal
carrier flow : 25 ml/main N2
injection volume: 2 µl

Duration of treatment / exposure:

6 weeks exposure for 10 animals per group for interim sacrifice and 13 weeks exposure for final sacrifice.

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 30, 125, 500 mg/kg/day
Basis:
no data

No. of animals per sex per dose:

30 animals per sex per dose in four group and 10 animals per sex per dose for fifth group

Control animals:

yes

Details on study design:

The amounts administered were based the most recent individual weekly body weight values.
N-Butanol Animals number (sacrifice)
Group Dose(mg/kg /day) male Female
interim final interim final
I 0 10 20 10 20
II 30 10 20 10 20
III 125 10 20 10 20
IV 500 10 20 10 20
V Base Line 10 20 10 20

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
Cage side observations include clinical in File 1( attached below) were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

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: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during pretreatment and on week 13
- Dose groups that were examined: all groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to treatment and on the time of nacropsy
- Anaesthetic used for blood collection: Yes (carbon dioxide)
- Animals fasted: No data
- How many animals: 10 animals per sex per dose group
- Parameters checked in File 2 (attached below) were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to treatment from dose group V and on the time of nacropsy
- Animals fasted: No data
- How many animals: 10 animals per sex per dose group


URINALYSIS: Yes
- Time schedule for collection of urine: prior to treatment from dose group V and 3-5 days prior to sacrifice
- Metabolism cages used for collection of urine: Yes, for 4 hours
- Animals fasted: No data



OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)

Statistics:

The body weight, food consumption, clinicopathologic, and organ weight data were tested for homogeneity of variance by Bartlett's method. If data were found to be homogeneous difference between control and treatment means were tested for statistical significance by method of Dunnett.If data not found to be homogeneous, The method of Gill (modified Dunnett's ) was employed.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Treatment related ataxia first appeared in the high dose group during week 8. Ataxia and hyperactivity occurred in frequently during weeks 9 and 10. These sign increased to a weekly incidence of 32% and 29% for atxia and hypoactivity respectively. On set of ataxia and hyperactivity was about 2-3 minutes after dosing and duration was less then one hour.

Mortality:

mortality observed, treatment-related

Description (incidence):

Treatment related ataxia first appeared in the high dose group during week 8. Ataxia and hyperactivity occurred in frequently during weeks 9 and 10. These sign increased to a weekly incidence of 32% and 29% for atxia and hypoactivity respectively. On set of ataxia and hyperactivity was about 2-3 minutes after dosing and duration was less then one hour.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

No treatment related effect was present on body weight and weight gain.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

No treatment related effect was present on food consumption. Statistically significant difference between control and treated group and food consumption would occur sporadically,but no trend was observed.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

Total Lesions 1, 2, 4, 5 ( including chorioretinal hypoplasia) were seen as in Control, Low dose, mid dose, high dose, respectively.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

At interim sacrifice, RBC(p≤ .05), PCV and HCB,(p ≤.01) in high dose female were 5% less than thr control group. The RBC and PCV (p≤ .05) average for middle dose were also slightly ( 4% and 3% respectively) than control over ages.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

At interim sacrifice, lower cholesterol level (p≤ .05) in high dose males, higher neutrophill count (p≤ .05) in mid dose male and at final evaluation lower lymphocyte count(p≤ .05) , higher neutrophill count in low dose females were observed.

Endocrine findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Higher (p≤ .05) urine pH values in the low dose males at the interim evaluation and in low dose females at the final evaluation were observed.

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):

No apparent treatment related effect on organ weight value. The only statistically significant difference between control and high dose males was slightly(p≤ .05) higher thyroid weight. No dose response relationship was present.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

No treatment related lesion was observed in gross necropsy at the interim or final sacrifices or of the rats found dead or sacrificed in extremes.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

No treatment related lesion was observed at histopathologic evaluation. The diffuse subacute lymphadenitis of mendibular lymph node was visible grossly as red or enlarged lymph nodes. This is a commonly observed lesion in laboratory rats.

Histopathological findings: neoplastic:

no effects observed

Details on results:

At interim evaluation, RBC, PCV, and HGB averages in the high dose females were 5% below control averages. The difference were statistically significant but biologically significance is questionable.
HISTOPATHOLOGY: NON-NEOPLASTIC . - Parameters checked in File 4 (attached below) were showing incidence of lesion examined.
BODY WEIGHT AND WEIGHT GAIN: change in mean organ weight were examine as shown in file 3(attached below)

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

haematology

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Read-across justifications and data matrices are presented in IUCLID section 13.

Applicant's summary and conclusion

Conclusions:

Oral administration of normal butanol at 500 mg/kg/day produced ataxia and hyperactivity at maximum weekly incidence rate of 32% and 29% respectively. A slightly lower (compare to controls) RBC, PCV and HGB concentration present in the 500 mg/kg/day dose group females at the interim evaluation only may have been treatment related. No treatment related effect were observed at 30 mg/kg/day and 125 mg/kg/day.

Executive summary:

Based on the study results NOAEL was concluded to be 125 mg/kg bw/day.