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Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well conducted study although some critical data are only briefly described. Hematological, clinical chemical and urinalyses and histopathology are only briefly addressed in Quast et al. (1983) publication.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1977
Reference Type:
publication
Title:
Unnamed
Year:
1983
Reference Type:
secondary source
Title:
1,1-DICHLOROETHENE (VINYLIDENE CHLORIDE)
Author:
Benson B
Year:
2003
Bibliographic source:
Concise International Chemical Assessment Document 51, World Health Organisation 2003

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Principles of method if other than guideline:
-
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
1,1-dichloroethene was provided by Dow Chemical, USA.
Samples were analysed by gas chromatography.

Impurities Concentration (ppm)
vinyl bromide 4
vinyl chloride 3-50
trans-1,2-dichloroethene 138-1700
cis-1,2-dichchloroethene 24-680
1,1,1-trichloroethane 2-60
1,1,2-trichloroethane 48
Hydroquinone monomethyl ether (inhibitor) 2

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Spartan Laboratories, Haslett, Michigan
- Age at study initiation: 6-7 weeks
- Diet: ground commercial chow, ad libitum
- Water: ad libitum, tap water

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
Doses prepared daily
90 day-interim timepoint:
The nominal concentrations of VDC in the drinking water were 0, 60, 100 or 200 ppm (v/v). The actual mean ± SD 1,1-dichloroethene concentrations determined by gas chromatographic analysis, were 0, 68 ± 13, 106 ± 22 and 220 ± 35 ppm
The mean ± SD daily dosage level in mg/kg based on water consumption were 5.9 ± 0.6, 10.0 ± 1.2 and 19.3 ± 2.7 mg/kg for male and 7.5 ± 0.4, 12.6 ± 1.1 and 25.6 ± 2.4 mg/kg for female, corresponding to 60, 100 and 200 mg/L, respectively.

2-year timepoint:
Nominal concentrations: 50, 100, 200 ppm
Mean ingested doses: males: 7, 10 and 20 mg/kg/day; females: 9, 14, 30 mg/kg/day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gas chromatographic analysis
90 day timepoint:
Nominal concentrations: 0, 60, 100 and 200 mg/L
Measured concentrations (mean±SD) : 0, 68 ± 13, 106 ± 22, and 220 ± 35 mg/L
Duration of treatment / exposure:
2 years, interim endpoint: 90 days
Frequency of treatment:
treatment via drinking water; ad libitum
Doses / concentrationsopen allclose all
Dose / conc.:
60 mg/L drinking water
Remarks:
Doses / Concentrations:
60 mg/L
Basis:
nominal in water
Dose / conc.:
100 mg/L drinking water
Remarks:
Doses / Concentrations:
100 mg/L
Basis:
nominal in water
Remarks:
Doses / Concentrations:
200 mg/L
Basis:
nominal in water
No. of animals per sex per dose:
80 rats/sex for control group
48 rats/sex for each dosage level
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
The rats were observed at regular intervals for signs of toxicity.
Body weights were recorded weekly at first and then monthly
Hematologic measurements at months 6, 12, 18, and 24: total erythrocyte count, total and differential leukocyte count, packed cell volume and hemoglobin concentration.
Clinical chemical measurements at months 6, 12, 18, and 24: serum alkaline phosphatase activity, serum glutamic pyruvic transaminase activity, and levels of urea nitrogen in the blood.
Urinalyses at months 6, 12, 18, and 24: specific gravity, pH, glucose, ketones, bilirubin, occult blood, and protein.
Sacrifice and pathology:
Complete gross pathologic examination of all animals
Weights of brain, heart, liver, kidney, and testes of sacrificed rats
Organs and tissues from all rats preserved in formalin for histopathologic examination. Special attention was given to grossly observed tumors and all such lesions were included in the tissues saved for histopathologic evaluation.
Other examinations:
No data
Statistics:
Hematology, clinical chemistry, organ weight and body weight data: analysis of variance and Dunnett's test
Tumor incidence: Fisher exact probability test
The level of significance chosen for all cases is p < 0.05

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Except for occasional statistcally significant differences in the cumulative mortality percentages, the mortality among the test animals was comparable to the controls
Mortality:
no mortality observed
Description (incidence):
Except for occasional statistcally significant differences in the cumulative mortality percentages, the mortality among the test animals was comparable to the controls
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Occasionally occuring statistically significant differences (increases and decreases) were neither dose-related nor time-related and were not considered to be related to the ingestion of 1,1-dichloroethene
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Occasionally occuring statistically significant differences (increases and decreases) were neither dose-related nor time-related and were not considered to be related to the ingestion of 1,1-dichloroethene
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No constistent or dose-related differences were observed in the clinical chemistry parameters or sulfhydryl levels evaluated
Urinalysis findings:
no effects observed
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:
effects observed, treatment-related
Description (incidence and severity):
minimal mid-zonal hepatocellular fatty changes and hepatocellular swelling
Histopathological findings: neoplastic:
no effects observed
Details on results:
The only pathological findings considered to be related to the ingestion of 1,1-dichloroethene, evident only upon microscopic examination, were those involving the liver. The hepatic changes, when present, were usually characterized by a minimal amount of mid-zonal hepatocellular fatty change in both male and female rats. In the male rats, only those in the 200 ppm group showed a statistically significantly increased incidence of hepatocellular fatty change. This group of rats also showed an increased incidence of hepatocellular swelling. A trend towards increased incidence of hepatic changes was observed in the male rats in the 100 ppm group. no exposure related hepatic changes were recognized in the 50 ppm group of male rats. Minimal hepatocellular fatty change (statistically significant at 100 and 200 mg/l groups) and hepatocellular swelling (statistically significant in all groups) were detected in female rats. No significant hepatocellular necrosis considered exposure-related was evident in either male or female rats at any of the dose levels. Based on the minimal nature of the hepatocellular swelling reported by the authors this effect is not considerd biologically significant and is not an adverse effect in the study.

Evaluation of the neoplasm data revealed an increased incidence of mammary gland fibroadenomas/adenofibromas in the females ingesting drinking water containing 50 ppm 1,1-dichloroethene. Since the incidence was within the normal range of the historical control data from this laboratory and was not dose-related, it was not considered to be related to the ingestion of 1,1-dichloroehtene. No other neoplastic types were observed which were significantly increased or decreased in either female or male rats. The total neoplasm incidence in the male and female rats i the various test groups was not different than the incidence in the control animals.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: minimal hepatocellular mid-zonal fatty change
Dose descriptor:
NOAEL
Effect level:
9 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: minimal hepatocellular mid-zonal fatty change
Dose descriptor:
LOAEL
Effect level:
19.3 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: minimal hepatocellular mid-zonal fatty change
Dose descriptor:
LOAEL
Effect level:
14 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: minimal hepatocellular mid-zonal fatty change

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Grossly observed tumors in rats given vinylidene chloride in drinking water for 2 years

Tumor

Dose (mg/L)

No. animals with tumors (or number of tumors/number of animals)

Percent of animals with tumors

Male

Female

Male

Female

Subcutaneous tumor (mammary and mid-cervical region)

Control

6/6

104/59

7.5

73.7

200

6/4

64/36

8.5

75.0

100

6/6

68/27

12.5

77.1

60

6/6

71/40

12.5

83.3

Subcutaneous tumor    (eye, ear, and head region)

Control

4

1

5.0

1.3

200

2

1

4.3

2.1

100

0

2

0

4.2

60

1

1

2.1

2.1

Subcutaneous tumor   (body or limb region)

Control

2

0

2.5

0

200

0

0

0

0

100

0

1

0

2.1

60

2

0

4.2

0

Nodular proliferation in Iiver (primary site)

Control

5

2

6.3

2.5

200

0

3

0

6.3

100

1

0

2.1

0

60

1

2

2.1

4.2

Liver (metastatic foci)

Control

0

1

0

1.3

200

0

0

0

0

100

0

0

0

0

60

I

0

2.1

0

Liver (diffuse tumor infiltrate and enlarged, associated with lymphoid)

Control

0

2

0

2.5

200

0

0

0

0

100

1

0

2.1

0

60

2

0

4.2

0

Kidney (primary site)

Control

2

1

2.5

1.3

200

0

0

0

0

100

0

1

0

2.1

60

1

0

2.1

0

Applicant's summary and conclusion

Conclusions:
The statistically significant hepatocellular midzonal fatty change is considered as a minimal adverse effect in this study. Accordingly, the NOAEL in male is 10 mg/kg-day and the LOAEL is 20 mg/kg-day; the NOAEL in female rats is 9 mg/kg-day and the LOAEL is 14 mg/kg-day. No significant increase in tumor incidence was noticed.
Executive summary:

Sprague-Dawley rats were exposed to vinylidene chloride orally in drinking water at 0, 50, 100 and 200 mg/L for up to 2 years.

The mean daily dosage level in mg/kg based on water consumption were 0, 7, 10 and 20 mg/kg for male and 0, 9, 14 and 30 mg/kg for female, corresponding to 0, 50, 100 and 200 mg/L, respectively.

The statistically significant hepatocellular midzonal fatty change is considered as a minimal adverse effect in this study. Accordingly, the NOAEL in male is 10 mg/kg-day and the LOAEL is 20 mg/kg-day; the NOAEL in female rats is 9 mg/kg-day and the LOAEL is 14 mg/kg-day.

No significant increase in tumor incidence was noticed in this study.