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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to OECD Guideline Study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Ethane, 2-Chloro-1,1-Dimethoxy-
IUPAC Name:
Ethane, 2-Chloro-1,1-Dimethoxy-
Constituent 2
Reference substance name:
97-97-02
IUPAC Name:
97-97-02
Constituent 3
Chemical structure
Reference substance name:
2-chloro-1,1-dimethoxyethane
EC Number:
202-624-0
EC Name:
2-chloro-1,1-dimethoxyethane
Cas Number:
97-97-2
Molecular formula:
C4H9ClO2
IUPAC Name:
2-chloro-1,1-dimethoxyethane
Test material form:
other: colourless liquid
Details on test material:
- Name of test material (as cited in study report): Chloroacetaldehyde dimethylacetal
- Physical state: colourless liquid
- Storage condition of test material: room temperature
- Container: brown glass bottle x2

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (U.K.) Limited, Manston, Kent
- Age at study initiation: 5-6 weeks
- Weight at study initiation: males: 137-168g, females: 127-159g
- Housing: polypropylene grid-floor cages suspended over trays lined with absorbent paper
- Diet: free access to food except during urine collection when food was withdrawn overnight
- Water: free access
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22°C
- Humidity (%): 37-68%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (control), 15.3, 51, 204, 0 (satellite), 204 (satellite) mg/kg/day
Basis:
nominal in diet
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
yes, concurrent vehicle
yes, plain diet

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: immediately before dosing and one and five hours after dosing during working week; immediately before dosing and one hours after dosing at weekends and public holidays; twice daily, morning and afternoon during treatment free period (one daily at weekends).

BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 7, 14, 21, 28

FOOD&WATER CONSUMPTION: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of study (day 28)
- Anaesthetic used for blood collection: Yes: Clotting time was assessed by "Hepato Quick" time using samples collected into sodium citrate solution (0.11 mol/L)
- Animals fasted: Yes
- How many animals: all from groups 1-4

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of study (day 28)
- Animals fasted: No
- How many animals: all of groups 1-4

URINALYSIS: Yes
- Time schedule for collection of urine: collected over a period of approx. 16h
- Parameters were examined:Volume, Specific gravity, pH, Protein, Glucose, Ketones, Bilirubin, Urobilinogen, Reducing substances, Blood
- animals: all
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes but normal hydration
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

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 specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
changes in kidney weights, liver weights
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
changes in kidneys, not relevant for humans
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
The administration of CADMA by oral gavage for a period of twenty-eight con-secutive days resulted in toxicologically significant changes at dose levels of 50 and 200 mg/kg/day. Increases in plasma alkaline phosphatase and bilirubin were apparent, although statistical significance was not achieved, possibly suggesting a slight liver change. This was supported by increases in liver weight in both sexes, however there were no histopathological changes. Kidney weights were also ele-vated in animals of both sexes treated with 200 mg/kg/day. Microscopic examina-tion of kidney sections revealed intracytoplasmic hyaline droplet formation in the proximaltubular epithelium of male rats treated with 50 and 200 mg/kg/day. These changes resemble a well documented (Alden C.L. (1986). A Review of Unique Male Rat Hydrocarbon Nephropathy. Toxicologic Pathology 14.1. pp. 109-111) hydrocarbon nephropathy which occurs in male rats but not in other species. This effect is therefore not indicative of a hazard to human health. Nevertheless, statisti-cally significant increases in kidney weight were also detected in females treated with 200 mg/kg/day and it is therefore possible that another slight renal change was also present in high dose animals.

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Organ weights, clinical chemistry

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral administration of the test material Chloroacetaldehyde dimethylacetal, to rats for a period of 28 consecutive days at dose levels of up to 200 mg/kg/day resulted in toxicologically significant changes at 50 and 200 mg/kg/day.
The NOEL is, therefore, considered to be 15 mg/kg/day. However, the changes at 50 mg/kg/day were confined to a kidney effect resembling hydrocarbon nephropathy which only occurs in male rats and is, therefore, not indicative of a hazard to human health.
Executive summary:

The test material Chloroacetaldehyde dimethylacetal was administered by gavage to three groups, each of five male and five female Sprague-Dawley CD strain rats, for 28 consecutive days, at dose levels of 15, 50 and 200 mg/kg/day (incorporating a correction factors to allow for 98% purity) comparable to the OECD Guideline Study 407. A control group of five males and five females was dosed with vehicle alone (arachis oil B.P.). Two satellite groups, each of five males and five females were treated with the high dose (200 mg/kg/day) or the vehicle alone throughout the 28 day study period and then maintained without treatment for a further 14 days.

Clinical signs, bodyweights, food and water consumptions were monitored during the study. Haematology, blood chemistry and urinalysis were evaluated for all main group animals during the final week of dosing. Parameters showing possible abnormalities were examined in satellite group animals at the end of the treatment-free period. All animals were subjected to a gross necropsy examination with histopathological evaluation of selected tissues.

Oral administration of the test material Chloroacetaldehyde dimethylacetal, to rats for a period of 28 consecutive days at dose levels of up to 200 mg/kg/day resulted in toxicologically significant changes at 50 and 200 mg/kg/day.

The NOEL is, therefore, considered to be 15 mg/kg/day. However, the changes at 50 mg/kg/day were confined to a kidney effect resembling hydrocarbon nephropathy which only occurs in male rats and is, therefore, not indicative of a hazard to human health.. The NOAEL therefore is 50 mg/kg bw.