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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1984
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Data from a preliminary study to select doses for a subsequent carcinogenicity study. Full range of parameters typical for repeat dose studies not examined

Data source

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
Unnamed
Year:
2001
Reference Type:
study report
Title:
Unnamed
Report date:
1995

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
To evaluate the toxic effects of repeated exposure to DEP by the dermal route and to select suitable dose levels for use in subsequent 2 year studies
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Diethyl phthalate
EC Number:
201-550-6
EC Name:
Diethyl phthalate
Cas Number:
84-66-2
Molecular formula:
C12H14O4
IUPAC Name:
1,2-diethyl benzene-1,2-dicarboxylate
Details on test material:
- Name of test material (as cited in study report): diethyl phthalate
- Physical state: liquid
- Analytical purity:>99%
- Stability under test conditions: 2 weeks
- Storage condition of test material: stored in amber glass bottles protected from light at room temperature
- Other: The stability of the bulk chemical was monitored periodically using GC. No degradation of the bulk chemical occurred.

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories Inc Gilroy CA USA
- Age at study initiation: approximately 42 days
- Weight at study initiation: range of mean weights males: 20.6-21.4g; females: 15.9-16.5g
- Fasting period before study: N/A
- Housing: individual
- Diet (e.g. ad libitum): yes, NIH07 open formula meal (Zeigler Brothers, Gardeners PA USA
- Water (e.g. ad libitum): yes, by automatic system
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-24 degrees C
- Humidity (%): 28-74%
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12h

IN-LIFE DATES: From: 1984-09-05 To: 1984-10-08

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: interscapular skin
- % coverage: not reported
- Type of wrap if used: N/A

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not reported
- Time after start of exposure: not reported

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0, 12.5, 25, 50 or 100ul
- Concentration (if solution): 100% used as supplied
- Constant volume or concentration used: yes/no: constant concentration
- For solids, paste formed: N/A

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses using reverse phase HPLC
Duration of treatment / exposure:
Ca 4 weeks
Frequency of treatment:
5 times /w (Monday -Friday)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 12.5, 25, 50 or 100ul
Basis:
nominal per unit area
No. of animals per sex per dose:
10 males & 10 females
Control animals:
yes, concurrent no treatment
Details on study design:

Animals randomly assigned to treatment groups using a computer generated randomisation procedure

Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 2 X daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: initially then weekly thereafter

DERMAL IRRITATION (if dermal study): No
- Time schedule for examinations:

BODY WEIGHT: Yes
- Time schedule for examinations: initially then weekly thereafter
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - complete histopathologic examinations conducted on all animals; Gross lesions, tissue masses and adrenal gland, brain, oesophagus, gall bladder , heart, kidney, lcolon, caecum, rectum, liver, lung, mammary gland, mandibular & mesenteric lymphnodes, nose, ovary, parathyroid gland, pituitary gland, prostate gland, salivary gland, seminal vesicles, skin ( site of application, control & other), duodenum, jejunum, ileum, spleen, sternum, stomach, testis, thymus, thyroid gland, trachea, urinary bladder & uterus
Other examinations:
No
Statistics:
Means & SDs & Williams or Dunnetts test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One female in the control group died. There were no clinical signs indicative of toxicity
Dermal irritation:
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
One female in the control group died. There were no clinical signs indicative of toxicity
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Final mean body weights of female mice given DEP were 5-7% heavier than controls
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute & relative liver weights were greater in females given 25 & 100 ul DEP than in controls.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: No effect of treatment

BODY WEIGHT AND WEIGHT GAIN: No effect of treatment

FOOD CONSUMPTION: No effect of treatment

ORGAN WEIGHTS: Absolute & relative liver weights were greater in females given 25 & 100 ml DEP than in controls.

GROSS PATHOLOGY: No effect of treatment

HISTOPATHOLOGY: NON-NEOPLASTIC: No effect of treatment

OTHER FINDINGS: None

Effect levels

Dose descriptor:
NOAEL
Effect level:
12.5 other: ul
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Increased liver weight (absolute & relative) in mice given 25 and 100 ul DEP.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study DEP applied neat to the skin of mice 5/7 days for 28 days the only effect was an increase in liver weight (absolute & relative) in those given 25 & 100 ul/31 & 123 mg. The NOAEL is considered to be 12.5 ul (15 mg).
Executive summary:

Under the conditions of this study DEP applied neat to the skin of mice 5/7 days for 28 days the only effect was an increase in liver weight (absolute & relative) in those given 25 & 100 ul/31 & 123 mg. The NOAEL is considered to be 12.5 ul (15 mg).