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Administrative data

Description of key information

In a 2-year drinking water study conducted with rats, the NOAEL was reported to be 9 mg/kg bw (Rampy et al. 1977,  Quast et al.1983). 
In a 90-day inhalation study conducted with rats and mice, a LOAEC of 6.25 ppm (= 26.7 mg/m3) was observed (NTP, 2015) for local effects. Systemic effects (nephropathy or cytoplasmic alterations in the liver) started to occur as of 12.5 ppm (= 53.4 mg/m3).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Principles of method if other than guideline:
-
GLP compliance:
not specified
Limit test:
no
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
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
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
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
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.
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
Critical effects observed:
not specified

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

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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
9 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
26.7 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
26.7 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated toxicity: oral

A 2-year drinking water study was performed on Sprague-Dawley rats (Rampy et al., 1977, Quast et al 1983). The average doses over the 2-year period 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 males 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.

NTP (NTP, 1982) performed a 14-day gavage study in Fischer 344 rats and B6C3F1 mice for selecting doses to be used in a 90-day gavage study in the same species. Doses selected were 5, 15, 40, 100 and 250 mg/kg. The 90-day study was used for selecting doses to be used in a 104-week gavage study in the same species. Doses selected were 1 and 5 mg/kg for rats; 2 and 10 mg/kg for mice. In the 104-week study, the absence of compound-related effects on survival, clinical signs or histopathological findings suggests that the animals of either sex could have tolerated higher doses. No drastic adverse effects were observed. The NOAEL is 10 mg/kg bw for mice and 5 mg/kg bw for rats i.e. the highest dose administered. Although, no significant effects were elicited in these 2 -year studies, it has been demonstrated that the liver was the target organ for chronic toxicity of 1,1 -dichloroethene by oral route, based on effects seen on both rats and mice following 90 days of exposure at doses above 40 mg/kg bw/d.

A 97-day oral study was also performed in Beagle dogs (Quastet al., 1983). No toxic effects were observed at any dose tested.

Repeated toxicity: inhalation

Male and female Sprague-Dawley rats were exposed to 1,1-dichloroethene by inhalation at 0, 100 and 300 mg/m3, 6 h/day, 5 days/week for exposure period of up to 18 months, followed by a 6-month recovery period (Quast et al.1986, Rampy et al 1977) . No exposure related changes in mortality, appearance and demeanour, body weight, clinical chemistry determinations, hematologic evaluations, and urinalysis were observed. Minimal hepatocellular fatty change in the midzonal region of the hepatic lobule was observed in both male and female rats after 6 and 12 months of exposure at both exposure levels. After 18 months of exposure, the midzonal hepatocellular fatty change was only observed in the female rats exposed to 150 mg/m3. After a 6 month post-inhalation period, the hepatic fatty change was no longer discernable. Accordingly the NOAEL for male rats in this study is 300 mg/m3, the NOAEL for female rats is 100 mg/m3, the LOAEL is 300 mg/m3.

Maltoni et al. conducted an inhalation study with male and female Swiss mice investigating the chronic toxicity and carcinogenicity of 1,1 -dichloroethene. Exposure was performed 4h/day, 4 -5 days/week and up to 52 weeks. After the exposure period, the mice were followed up till spontaneous death. The tested concentrations were 40 and 100 mg/m3 and the study design was similar to OECD guideline 451, yet with a treatment period of only 1 year, only 30 mice in the 40 mg/m3 group and only 2 levels of 1,1-dichloroethene exposure tested because of the excessive lethality in the higher dose groups. 100 mg/m3 was found to be the highest bearable dose by Swiss mice for long-term exposure. Doses of 800 and 400 mg/m3 for 2 days, and of 200 mg/m3 for 4 days (4 hours daily) caused death of an important proportion of the male animals. When it appeared that exposure to 800, 400 and 200 mg/m3 had to be withdrawn because of high mortality and severe toxic effects, the number of animals exposed to 100 mg/m3 was enlarged by adding a supplementary group, so that only 2 dose-levels (40 and 100 mg/m3) were selected for this long-term study. The main non-neoplastic finding in this study were degenerative changes in the kidneys in male (LOAEL 40 mg/m3) and female (LOAEL 100 mg/m3) mice. Nevertheless, because of several shortcomings of the study design and reporting, the results of this study were discarded in the overall risk assessment. This approach is in line with the EPA's toxicological review of 1,1 -dichloroethene (2003) in which it was stated that the study was rejected for the definition of the inhalation reference concentration because the animals were only exposed for 1 year and there was no evaluation of endpoints ant the termination of exposure. Thus the true incidence of the effects due to exposure to 1,1 -dichloroethene could not be determined.

In the framework of the US National Toxicological program (NTP, 2015) groups of 5 males and 5 females Fischer 344 rats and B6C3F1 mice were exposed by whole body inhalation to vinylidene chloride vapor at concentrations of 0, 25, 50, 100, 200 or 400 ppm, 6 hours per day, 5 days per week for 16 days (rats) or 17 days (mice). The studies were performed following a standardized protocols equivalent or similar to OECD 412 guideline and in compliance with Food and Drug Administration Good Laboratory Practice Regulations (21 CFR, Part 58).

All male mice exposed to 100 ppm or greater died within the first 4 days of exposure. All females exposed to 200 or 400 ppm were found dead following exposure on day 1. One 50 ppm male and one 100 ppm female were removed dead before exposure on day 5. Mean body weights of 25 and 50 ppm male mice were less than those of the chamber control group. Lethargy and abnormal breathing occurred in 50 and 100 ppm males. In all surviving groups of exposed females, lung weights were significantly greater than those of the chamber controls, and the liver weights of 50 and 100 ppm females were significantly greater than those of the chamber controls. Necrosis of the respiratory epithelium of the nose occurred in all mice exposed to 200 or 400 ppm and in all 100 ppm males. In the liver, centrilobular necrosis occurred in all males and females exposed to 100 ppm or greater; in addition, regeneration occurred in the four 100 ppm females that survived to the end of study. In the kidney, proximal renal tubule necrosis and granular casts occurred in all exposed males. No NOAEC or LOAEC was derived in the report however, based on the above-mentioned results, the LOAEC value can be estimated to be 25 ppm for mice of both sexes after reapeated inhalation dose exposure and under the experimental conditions described in the report (expert judgement).

All male and nine of 10 female rats in the 200 and 400 ppm groups were found dead by day 2; one female in the 400 ppm group was found dead on day 4. All other rats survived until the end of the study except one 25 ppm male was removed from the study due to chylothorax (nonexposure-related condition). The mean body weight gain of 100 ppm females was significantly less than that of the chamber controls. All females and nine of 10 males exposed to 200 or 400 ppm became lethargic, while all females and four of five males exposed to 400 ppm developed ataxia. Kidney weights of all surviving groups of exposed males and females were significantly greater than those of the chamber controls. In the liver, centrilobular necrosis was associated with early deaths in male and female rats exposed to 200 or 400 ppm, and centrilobular cytoplasmic alteration of hepatocytes occurred in all exposed male and female rats that survived to terminal kill. The incidences of renal tubule casts in the renal papillae of 200 and 400 ppm rats were significantly increased. No NOAEC was derived in the report however, based on the above-mentioned results, the NOAEC value can be estimated to be 100 ppm for rats of both sexes after reapeated inhalation dose exposure and under the experimental conditions described in the report (expert judgement).

NTP (NTP, 2015) has also performed two 3 -month studies following standardized protocols equivalent or similar to OECD 413 guideline and in compliance with Food and Drug Administration Good Laboratory Practice Regulations (21 CFR, Part 58) where groups of 10 male and 10 female Fischer 344 rats and B6C3F1 mice were exposed by whole body inhalation to vinylidene chloride vapor. Rats and mice were individually exposed at concentrations of 0, 6.25, 12.5, 25, 50, or 100 ppm, the highest concentration tested in rats and in female mice only, 6 hours per day, 5 days per week for 14 weeks (i.e. 70 days of exposure).

In the study performed with rats, additional clinical pathology groups of 10 male and 10 female rats were exposed to the same concentrations for 23 days. All rats survived until the end of the study. Mean body weights of exposed groups were similar to those of the chamber control groups. Sorbitol dehydrogenase activities were increased in 100 ppm females on day 3 and 100 ppm males and 50 and 100 ppm females on day 23. Alanine aminotransferase activities were increased on day 3 in 50 and 100 ppm male rats and on day 23 in 100 ppm male rats. Kidney weights of 12.5 ppm or greater females were significantly greater than those of the chamber controls. In males, sperm motility was decreased and spermatid/g testis and total spermatid/testis were lower at 100 ppm than those of the chamber control groups. No treatment-related effects were observed in females. These data suggest that vinylidene chloride may be a reproductive toxicant in male, but not female rats. A combination of lesions in the nasal epithelium of male and female rats including olfactory epithelium atrophy, mineralization, and necrosis and turbinate atrophy occurred with generally increasing severity with increasing exposure concentration. In the liver, the incidences of centrilobular cytoplasmic alteration were significantly increased in males exposed to 12.5 ppm or greater, and cytoplasmic vacuolization occurred in all 50 and 100 ppm females.

No NOAEC or LOAEC was derived in the report however, based on the above-mentioned results, the LOAEC value can be estimated to be 6.25 ppm for rats of both sexes after reapeated inhalation dose exposure and under the experimental conditions described in the report (expert judgement). The basis for the LOAEC are the local effects observed following exposure to 6.25 ppm. As the systemic effects (cytoplasmic alterations in the liver) only occur at 12.5 ppm or higher, 6.25 ppm can be considered as the NOAEC for systemic effects. A concentration of 6.25 ppm corresponds to 26.7 mg/m3 1,1 -dichloroethylene.

In the study performed with mice, two 50 ppm males and four 100 ppm females died during the first week of the study. The mean body weights of all exposed groups of females and of males exposed to 12.5 ppm or greater were significantly less than those of the chamber control groups. Exposure concentration-related decreases in the erythrocyte counts, hemoglobin concentrations, and hematocrit values occurred at the end of the study in 12.5, 25, and 50 ppm male mice. Female mice had decreased erythrocyte counts in the 50 and 100 ppm groups. In addition, hemoglobin concentration and the hematocrit value were decreased in 50 ppm female mice. Absolute kidney weights of all exposed groups of males were significantly less than that of the chamber control group. Absolute and relative liver weights of 12.5 ppm or greater females and absolute and relative kidney and lung weights of 100 ppm females were significantly greater than those of the chamber controls. In males, decreased cauda epididymis weights at 25 and 50 ppm and total sperm/cauda epididymis in all vinylidene chloride-exposed groups were observed. No treatment-related effects were observed in females. These data suggest that vinylidene chloride may be a reproductive toxicant in male, but not female mice. In male mice, the incidences and severities of nephropathy were significantly increased in the 12.5, 25, and 50 ppm groups, and two 50 ppm males had renal tubule necrosis and protein casts. The incidence of respiratory epithelium squamous metaplasia of the larynx was significantly increased in the 50 ppm males. In female mice, laryngeal lesions consisted of necrosis and respiratory epithelium hyperplasia and squamous metaplasia and occurred primarily in the 100 ppm group. Exposure-related lung lesions were limited to 100 ppm female mice and consisted of bronchial epithelium necrosis and histiocytic inflammation. The incidences of nasal necrosis of the respiratory epithelium and atrophy of the turbinate were significantly increased in 100 ppm females. The incidences of necrosis and hypertrophy of the liver were significantly increased in 100 ppm females, and necrosis occurred in two 50 ppm males. No NOAEC or LOAEC was derived in the report however, based on the above-mentioned results, the NOAEC (systemic) value for male can be estimated to be 6.25 ppm and, for females, the LOAEC (systemic) value can be estimated to be 6.25 ppmn both after reapeated inhalation dose exposure and under the experimental conditions described in the report (expert judgement). The basis for the LOAEC are the local effects observed following exposure to 6.25 ppm. As the systemic effects (nephropathy) only occur at 12.5 ppm or higher, 6.25 ppm can be considered as the NOAEC for systemic effects.

A concentration of 6.25 ppm corresponds to 26.7 mg/m31,1 -dichloroethylene.

Other inhalation studies with exposure durations ranging from 30 days to 12 months and also with other animal species have been published. The results of these studies were well in line with the abovementioned key study.

 


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

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Study showing nephropathy in mice at concentrations of 53.4 mg/m3 (=12.5 ppm) or higher.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Study showing olfactory epithelium necrosis at concentrations of 26.7 mg/m3 (= 6.25 ppm) or higher.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Relevant for classification for specific target organ toxicity (repeat exposure) are the oral NOAEL of 9 mg/kg/day (Quast et al. 1983), and the inhalation LOAEC of 6.25 ppm (26.7 mg/m3/6h/day) (NTP, 2015).

Table 3.9.1 of Annex I of EU regulation 1272/2008 states that substances should be classified in Category 1 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant and/or severe toxic effects. According to 3.9.2.3 of Annex I of EU regulation 1272/2008, classification is determined by expert judgement, on the basis of the weight of all evidence available. Moreover, the guidance values provided in Table 3.9.2.of Annex I of EU regulation 1272/2008 refer to effects seen in a standard 90-day toxicity study conducted in rats which can be extrapolated to equivalent guidance values for toxicity studies of greater or lesser duration (3.9.2.9.5).

The guidance value for STOT-RE Cat. 1 classification for the oral route is 10 mg/kg bw/d. For the inhalation of vapours, the guidance value is 0.2 mg/L/6h/d.

The oral NOAEL of 9 mg/kg/d originates from a chronic studies (≥ 18 months of treatment) (Quast et al. 1983), and was defined

based on the occurrence of minimal hepatic changes in the liver at higher doses/concentrations which are completely reversible after termination of exposure. These findings warrant a classification as STOT-RE Cat. 2 for the oral route.

The inhalation LOAEC of 26.7 mg/m3/6h/d, or 0.0267 mg/L/6h/d originates from the 90 day study in rats (NTP, 2015).

Significant effects of olfactory epithelium necrosis was observed as from 12.5 ppm (0.0534 mg/L/6h/d) and the effects increased with increasing exposure concentrations. Based on these findings, classification of 1,1 -dichloroethene as STOT-RE Cat. 1 for the inhalation route is proposed, with the nose as the target organ.

 

Because no data is available about the dermal route of exposure and because repeated dermal exposure is uncommon for 1,1-dichloroethene, no classification for repeated exposure via the dermal route is proposed.