1,1-dichloroacetone

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

1993

Reliability:

4 (not assignable)

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1993

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,1-dichloroacetone

EC Number:

208-175-7

EC Name:

1,1-dichloroacetone

Cas Number:

513-88-2

Molecular formula:

C3H4Cl2O

IUPAC Name:

1,1-dichloropropan-2-one

Constituent 2

Reference substance name:

1,1-Dichloro-2-Propanone

IUPAC Name:

1,1-Dichloro-2-Propanone

Test material form:

other: colourless oily liquid

Details on test material:

purity 98%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Charles River Laboratories, 70 days old, 200-300 g.
Acclimatisation: 2 weeks.
26°C, 40-50% humidity, 12:12 light:dark cycle.
Purina certified Chow 5002, tap water ad libitum.
Identified by ear tag, randomized into treatment groups.
Start weight female 255-263 g, male 406-423 g.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

1 mL corn oil per kg body weight

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC analysis

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily for 90 days

Doses / concentrations

Remarks:

Doses / Concentrations:
10, 20, 40, 80 mg/kg/day
Basis:
other: actual in vehicle

No. of animals per sex per dose:

10 male and 10 female

Control animals:

yes, concurrent vehicle

Details on study design:

all rats were observed twice daily, bodyweights recorded weekly, water consumption three times a week, food consumption weekly

Positive control:

no

Examinations

Observations and examinations performed and frequency:

The following organs and tissues were collected at necropsy and preserved in 10%
buffered formalin: skin, mammary glands, thigh muscle, sciatic nerve, mandibular lymph
nodes, mesenteric lymph nodes, femur (including bone marrow), tongue, salivary gland,
thymus, trachea, lung with bronchi, esophagus, stomach, duodenum, jejunum, ileum,
cecum, colon, rectum, liver, pancreas, spleen, kidneys, adrenals, urinary bladder, seminal
vesicles, prostate, testes (including epididymis), ovaries, uterus, preputial or clitoral
glands, Zymbal's gland, nasal turbinates, brain, pituitary, thyroiWparathyroid, heart, and
aorla. Subsequently, tissues taken from 5 males and 5 females of the control group as
well as all surviving animals in the highest dose groups were trimmed, embedded in
paraffin, sectioned at 5 pm, and stained with hematoxylin and eosin. The tissues were
initially examined by a veterinary pathologist and subsequently, the liver, kidneys, and
stomach, (identified as possible target organs) were examined in all of the lower dose
groups.
Inflammatory and degenerative lesions were graded according to severity using a
scale of one to four (minimal, mild, moderate, or marked)and the data were tabulated by
individual animal and then summarized by group.

Sacrifice and pathology:

Animals were euthanized following blood collection via exsanguination and
immediately necropsied. The necropsy included gross examination of the animals'
external surface and orifices, external surface of the brain, all organs, and the thoracic,
abdominal. and pelvic cavities. The adrenal glands, brain (including the brain stem),
gonads, heart, kidneys, liver, lungs, spleen, and thymus were weighed.

Other examinations:

The following serum clinical chemistry determinations were accomplished using a
Baker Encore centrifugal analyzer: blood urea nitrogen (BUN), calcium (CA), creatinine
(CRE), total cholesterol (CHO), glucose (GLU), lactate dehydrogenase (LDH), inorganic
phosphorus (PO4), aspartate aminotransferase (AST), and alanine aminotransferase
(ALT). Appropriate normal and abnormal whole blood and serum controls were evaluated
at each assay.

Statistics:

Data were analyzed by sex using a one-factor (dose) analysis of variance (ANOVA)
method to test for normal distribution of data (p <= 0.05), the difference between the
control and treatment groups was further analyzed, using the Tukey's multiple
comparison procedure for overall differences. Due to the high variability of some of the
clinical chemistry and organ weight measures, a nonparametric analysis of variance
procedure, i.e.the Kruskal-Wallis test, was also employed to determine differences
among the dose groups. The statistical significance of histopathological occurrences was
tested using Fisher's One-tail test comparing each treatment group to controls.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

No rats died during the study.

Mortality:

mortality observed, treatment-related

Description (incidence):

No rats died during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

decrease

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

no effect

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

increase: serum enzymes

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

increase: serum enzymes

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

increase for liver and kidneys

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

All gross lesions were considered to be incidental findings and not related to DCP exposure.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

liver, forestomach, kindneys

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

bile duct hyperplasia

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Groups of 10 male and 10 female Sprague-Dawley rats were administered 1,1-Dichloro-2-Propanone in corn oil by gavage at 0, 10, 20, 40, or 80 mg/kg/day for 90 consecutive days. No treatment related mortality was observed during the study, however: liver, forestomach and kidney toxicity was evident. Based on liver lesions and biochemical changes it was concluded that there was no experimentally definable NOAEL.

Executive summary:

Oral (gavage) administration of DCP in corn oil at doses of 0, 10, 20, 40, and 80

mg/kg/day for 90 days to male and female rats did not affect mortality however liver and

forestomach toxicity were observed in both sexes while an increased incidence of kidney

changes were apparent only in the males.

The liver changes included a dose-dependent increase in cytoplasmic alteration,

cytomegaly, karyomegaly, and bile duct hyperplasia which occurred without substantial

hepatocellular necrosis and were probably due to a direct treatment-related

metabolic/biochemicaI stimulus with enhanced cellular metabolism and enzyme induction.

The hepatic cytomegaly present in the highest dose groups was consistent with the

increased liver weights that were observed in both females and males.

While the microscopic changes noted in the liver appeared similar in females and

males, there were differences in the serum enzyme (ALT, AST, and LDH) activities.

These enzymes were elevated in females, but decreased in males. While the mechanism

responsible for this sex difference cannot be stipulated, this paradoxical suppression of

metabolic enzymes is probably not an artifact of the kinetic assays since similar findings

have been documented in prior studies with related chemicals (Bercz, unpublished

results).

DCP induced hyperkeratosis and epithelial hyperplasia of the forestomach in all

treated animals at 80 mg/kg/day and in over 80% of those in the 40 mg/kg/day groups.

There appears to be a sharp threshold for this effect since these changes were not

observed at the two lowest doses or in the controls. .Ulcerations of the forestomach were

obsewed only at the highest dose level in both females and males. Lesions of this

nature, in which there is a noted increase in the number of cells and keratin production,

are generally indicative of direct chemical irritation to the mucosal surface.

The incidence of spontaneous progressive nephropathy which is known to be

caused in rats by stress or genetic susceptibility.(' displayed a treatment related

incidence increase in the high dose males; however, it appeared randomly in females.

The results of this study clearly indicate that the liver and forestomach are primary

target organs for DCP toxicity with microscopic lesions being observed in both male and

female rats. In addition, statistically significant changes in select serum enzymes were

found at all dose levels. Based on the presence of the various changes at all dose levels,

it was concluded that there was no NOAEL in this study.