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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: OECD 411
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no deviation from OECD guideline (OECD 411). Not GLP.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD 411
Deviations:
no
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
- Name of test material (as cited in study report): DGA
- Substance type: clear, colorless
- Physical state: liquid
- Lot/batch No.: 9F10
- Expiration date of the lot/batch: 15 July 2001
- Stability under test conditions: stability information was not provided
- Storage condition of test material: room temp

Administration / exposure

Route of administration:
dermal
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: between 10 and 20% of the body surface
- Type of wrap if used: gauze pad, rubber dam and an elastic bandage
- Time intervals for shavings or clipplings: minimum of twice weekly


REMOVAL OF TEST SUBSTANCE
- Washing (if done): gently cleansed with gauze soaked in warm water and gently dried
- Time after start of exposure: 6h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml/kg bw /d
- Concentration (if solution): 0 - 17- 87- 175 mg/kg bw/d
- Constant volume or concentration used: yes


VEHICLE = deionized water
- Amount(s) applied (volume or weight with unit): 0.5 ml/kg bw/d
- Lot/batch no. (if required): 071099, 201099, 011199, 091199, 171199, 221199, 031299, 081299, 151299, 171299, 281299
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
nominal concentration (mg/kg bw/d): 0 - 50 - 250 - 500 respectively
actual concentration (mg/kg bw/d): 0 - 17 - 87 - 175 respectively

Duration of treatment / exposure:
approximately 6h

Frequency of treatment:
once daily, 90 consecutive days

Doses / concentrations
Remarks:
Doses / Concentrations:
17, 87, 175 mg/kg bw
Basis:
nominal in water
No. of animals per sex per dose:
10 male and 10 female rats per dose

Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: once daily


BODY WEIGHT: Yes
- Time schedule for examinations:
at the time of randomisation
prior to dose administration on day 1
weekly (after that)
on day 91 (fasted)


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (weekly)


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION: No data


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before treatment + prior to terminal sacrifice
- Dose groups that were examined: all animals


HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 91, prior to terminale sacrifice
- Anaesthetic used for blood collection: Yes, CO2
- Animals fasted: Yes , overnight
- How many animals: all surviving animals (= all animals, 80)
- Following parameters were examined.
* Hematology: differential white blood cell count, hematocrit, hemoglobin, mean corpuscular hemoglobin,
mean corpuscular hemoglobin concntration, mean corpuscular volume, platelet count, red blood cell count and morphology,
white blood cell count
* Coagulation: prothrombin time, acctivated partial thromboplastin time


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:on day 91, prior to terminale sacrifice
- Animals fasted: Yes , overnight
- How many animals: all animals (80)
- Following parameters were examined:
* serum clinical chemistry: alanine aminotransferase, albumin, albumin/globulin ratio (calculated), aspartate aminotransferase, calcium,
chloride, cholesterol, creatinine, creatine phosphokinase, globulin (calculated), glucose, phosphorus, potassium, sodium, total bilirubin,
total protein, triglycerides, urea nitrogen


URINALYSIS: Yes
- Time schedule for collection of urine: on day 90, urine was collected overnight
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Following parameters were examined:
* volume, specific gravity, appearance/color, semi-quantitative estimation: pH, protein, glucose, ketone, urobilinoen, bilirubin,
blood, leukocytes, nitrites, microscopic examination of spun deposit

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on day 28 and day 90 during treatment
- Dose groups that were examined: all
- Battery of functions tested: observation of animals / sensory activity / grip strength / motor activity / other: loss of righting reflex,
spontaneous locomotor activity, right pupil examination, various reflex responses


OTHER:

Sacrifice and pathology
GROSS PATHOLOGY: Yes
external surface of the body, all orifices, cranial, thoracic and abdominal cavities together with their content

HISTOPATHOLOGY: Yes
gross abnormalities, adrenals, aorta, whole brain, cecum, colon, duodenum, epididymides, esophagus, exorbital lachrymal gland,
eyes w/optic nerve, femur, fat (mesentery), heart, ileum, jejunum, kidneys, liver, lungs with mainstem bronchus, mammary gland(s), mesenteric
lymph nodes, ovaries, pancreas, pituitary, prostate, rectum, salivary glands (mandibular lymph nodes), sciatic nerve, seminal vesicle(s),
skin (with subcutis from a site other than the treated site), spinal cord at three levels - cervical, midthoracic, lumbar - spleen, sternum with bone
marrow, stomach, testes, thigh musculature (skeletal muscle), thymus, thyroids/parathyroids, tongue, trachea, treated site (dorsal thoracic region
with subcutis), urinary bladder, uterus, vagina

Statistics:
evaluation of equality of means: one-way analysis of variance usiing the F distribution to assess statistical significance
is differences between the means are statistically significant, Dunnett's test was used to determine the degree of significance.

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 17 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: dermal effects
Dose descriptor:
NOAEL
Effect level:
>= 175 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Application of DGA to an intact cutaneous site for approximately six hours, once daily for 90 consecutive days to male and female Sprague-Dawley rats, results in ulceration, epidermal hyperplasia, fibrosis and/or inflamation at doses of 87 and 175 mg/kg bw/d. These changes represent local irritation following topical administration.
Based on the results of the study, the dermal NOAEL was at least 17 mg/kg bw/d while the systemic NOAEL was at least 175 mg/kg bw/d.