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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study, published in a peer-reviewed literature, adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Observations on the oral administration of vinyl chloride in rats.
Author:
Feron, V.J., Speek, A.J., Willems, M.I., van Battum, D. and de Groot, A.P.
Year:
1975
Bibliographic source:
Fd Cosmet Toxicol 13:633-638.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): vinyl chloride monomer (VCM)
- Substance type: organic
- Physical state: gaseous
- Supplier: Akzo Zout Chemie, Rotterdam, The Netherlands
- Melting point: -153.8 C
- Boiling point: 13.37 C
- Density: 0.9106

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: a colony of Central Institute for Nutrition and Food Reseach (CIVO), TNO, Zeist, The Netherlands
- Age: weaning
- Housing: in wire-screen cages in groups of three in air-conditioned inhalation chamber
- Diet: institute stock diet, ad libitum
- Water: tap water, ad libitum
- Initial body weights: mean 44 g for both males and females

ENVIRONMENTAL CONDITIONS:
- Temperature: 22-24 C
- Relative humidity: 60%

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
soya oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Solutions of VCM in soya bean oil were prepared either by bubbling VCM gas through the oil or by injecting liquid VCM into the oil.
VEHICLE:
- Justification for use and choice of vehicle (if other than water): as VCM is lipophilic, VCM was administed as a solution in edible oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the solutions with regard to their VCM content was tested in storage experiments under various conditions either by weighing the vessels containing the solutions or by gas chromatography. The VCM solutions were also examined for polymerization products of VCM and for reaction products of VCM with unsaturated fatty acid moieties of the oil.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 100 or 300 mg/kg
Basis:
other: nominal in soya oil
No. of animals per sex per dose:
15/sex/dose
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT:
- Individual body weights were recorded weekly.
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food intake of each group was measured in weeks 1-4 and in weeks 11 and 12.
HAEMATOLOGY:
- Haematological indices (blood clotting time, haemoglobin content, packed cell volume and counts of erythrocytes and total and differential leucocytes) and biochemical blood values (sugar, urea nitrogen, total serum protein, serum albumin and activities of glutamic-oxalacetic transminase (GOT)m, glutamic-pyruvic transaminase (GPT) and alkaline phosphatase) were recorded terminally in ten males and ten females of each group.
CLINICAL CHEMISTRY:
- The following histochemical enzyme determinations were carried out on cryostat sections of liver specimens from five males and five females: alkaline phosphatase, acid phosphatase, adenosine monophosphatase, adenosine triphosphatase and glucose-6 phosphatase.
URINALYSIS:
- Kidney funcion (specific gravity and activity of GOT in urine) was examined in week 13 in ten males and ten females of the control and top-dose group. Also in week 13, urine examinations, including appearance, pH, glucose, protein, occult blood, ketones and microscopic constituents, were conducted upon pooled uring samples from ten males and ten females of each group.
Sacrifice and pathology:
SACRIFICE:
- In week 14 all rats were killed by decapitation
GROSS PATHOLOGY:
- All rats were examined for gross changes. The heart, kidneys, liver, spleen, brain, gonads, thumus, thyroid and adrenals were weighed.
HISTOPATHOLOGY:
Samples of heart, kidneys, liver, spleen, brain, gonads, thumus, thyroid, adrenals and other organs were preserved in 10% buffered formalin. Detailed microscopic examination was performed on all organs of the high dose group and on the controls. Paraffin sections stained with haematoxylin-eosin were prepared from the weighed organs and from the lungs, salivary glands, trachea, thoracic aorta, skeletal muscle, axillary and mesenteric lymph nodes, ceruminous glands, pancreas, urinary bladder, sternum with bone marrow, prostate, epididymis, uterus, mammary glands, oesophagus, fore and glandular stomach, duodenum, ileum, caecum and colon. In rats given the other dose levels only the liver was examined microscopically.
Other examinations:
Electron microscopy on small pieces of liver from one male and one female control rat and from two males and two females from each test group was performed.
Statistics:
Wilcoxon's test

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:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Gavage administration of VC solutions in soybean oil at levels up to 300 mg/kg/day did not cause any noticeable changes in appearance or behavior,

BODY WEIGHT AND WEIGHT GAIN
Gavage administration of VC solutions in soybean oil at levels up to 300 mg/kg/day did not cause any noticeable changes in body weight gain

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Gavage administration of VC solutions in soybean oil at levels up to 300 mg/kg/day did not cause any noticeable changes in food intake.

HAEMATOLOGY
The total number of white blood cells and the sugar content of the blood were slightly decreased in the 100 and 300 mg/kg/day groups

CLINICAL CHEMISTRY
Serum GOT and GPT activities and of urinary GOT activity were decreased in males receiving 300 mg/kg/day. There were no other significant changes in the hematological or biochemical indices.

ORGAN WEIGHTS
The relative liver weights in males and females showed a tendency to increase with increasing doses of VC, but was only statistically significant at the highest dose level.  In addition, a dose-related decrease in the relative adrenal weight occurred in males, but was only statistically significant at the highest dose level.  The other organ weights recorded were closely comparable in all groups.

HISTOPATHOLOGY: NON-NEOPLASTIC
Minimal histologic changes in the liver, seen as one or a few foci of 40-70 hyperbasophilic hepatocytes occurred in one male and one female rats in both the 100 and 300 mg/kg/day groups.  Electron microscopic examination of the liver showed hypertrophy of the endoplasmic reticulum in hepatocytes of animals given the highest dose.  Lower dose levels were not examined.

OTHER FINDINGS:
Randomly distributed histopathological changes unrelated to treatment inluded small accumulations of reticulo-endothelial cells in the liver, focal tumular nephrosis, a slight degree of nephrocalcinosis, parasites in teh renal pelvis and urinary bladder, early signs of chronic respiratory disease in teh lungs, granulomatous pneumonic foci, medial hypertrophy of medium-sized pulmonary arteries, "morphological" activation of the thyroid gland, focal myocarditis, transformation of pancreatic acini into duct-like structures, "sqaumous"metaplasia of the epithelium lining excretory ducts of the sublingual salivary gland and slight prostatitis.

Effect levels

Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: 100 mg/kg/day - decreased leukocytes and blood sugar 300 mg/kg/day - Same effects as 100 mg/kg/day. Decreased serum GOT and GPT and urinary GOT. Increased liver/bw, adrenal/bw, hypertrophy of endoplasmic reticulum of liver

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1. Mean results of administering 0-300 mg VCM/kg body weight/day to rats by gavage on 6 days/week for 13 weeks, showing diferences of possible toxicological significance between test and control animals.

Values for males given VCM in doses (mg/kg) of

Values for females given VCM in doses (mg/kg) of

Parameter affected

0

30

100

300

0

30

100

300

Total leucocytes (103/mm3)

18.5

18.8

17.0

16.5

17.3

17.6

14.6*

14.8*

Blood sugar (mg/100 ml)

88

84

78**

77**

89

88

74***

79**

Serum:

GOT (R-Fu)

GPT (R-Fu)

228

53

217

49

224

48

201*

45*

227

42

212

38

212

38

200

39

Urinary GOT (R-Fu)

30

NE

NE

22*

16

NE

NE

18

Liver weight (g/100 g bw)

3.51

3.60

3.74

3.76*

3.32

3.34

3.51

3.71***

Adrenal weight (g/100 g bw)

0.0158

0.0147

0.0143

0.0133*

0.0247

0.0241

0.0239

0.0244

Foci of hyperbasophilic hepatocytes (number of affected rats/group)

0

0

1

1

0

0

1

1

RER in liver cells

Normal

NE

NE

Ht

Normal

NE

NE

Ht

GOT = glutamic-oxalacetic transaminase

GPT = glutamic-pyruvic transaminase

R-Fu = Reitman-Frankel units

NE = not examined

RER = rough endoplasmic reticulum

Ht = hypertrophic

Values are the means of at least ten rats, except for the electron-microscope observations on the liver which were made on one control and two test animals. Those marked with asterisks differ significantly (Wilcoxon's test) from those of the controls: *P < 0.05, **P < 0.01, *** P < 0.001



Applicant's summary and conclusion