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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
no
Principles of method if other than guideline:
NDC was administered as a particulate aerosol by inhalation at target concentrations of 0, 1.0, 5.0, and 10.0 mg/m3 to four groups of 10 male and 10 female Sprague-Dawley rats each. The rats were exposed 6 hours per day, 5 days per week for four weeks.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethyl naphthalene-2,6-dicarboxylate
EC Number:
212-661-4
EC Name:
Dimethyl naphthalene-2,6-dicarboxylate
Cas Number:
840-65-3
Molecular formula:
C14H12O4
IUPAC Name:
dimethyl naphthalene-2,6-dicarboxylate
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

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 Breeding Laboratories, Inc., Portage, MI
- Age at study initiation: approximately 6 weeks of age
- Housing: The rats were individually housed in stainless steel cages measuring 15.5 x 17.0 x 15.8 cm during the 4-week quarantine period. The rats were confined in inhalation cages measuring 13.0 x 20.0 x 27.5 cm during the exposure phase. The cages were suspended over excrement pans. The pans were fitted with deotized cage boards, except during the exposure.
- Diet (e.g. ad libitum): Purina Rodent Chow 5001 supplied from a reverse-osmosis (RO) purifier by an automatic watering system was provided ad Iibitum, except during the inhalation exposures.
- Water (e.g. ad libitum): Water supplied from a reverse-osmosis (RO) purifier by an automatic watering system was provided ad Iibitum, except during the inhalation exposures.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 22°C
- Humidity (%): 40%
- Photoperiod (hrs dark / hrs light): Fluorescent lighting was provided for 12 hours followed by 12 hours of darkness.

IN-LIFE DATES: From: 24 May 1988 To: 22 June 1988

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
not specified
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: MMAD (mean of 4 samples): Low Exposure: 5.54 ± 0.174; Medium Exposure: 5.05 ± 0.488; High Exposure: 5.56 ± 0.495
Min/Max: Low Exposure (5.28/5.66) ; Medium Exposure (4.57/5.73); High Exposure (5.11/6.19)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- System of generating particulates/aerosols: The generator was a dry materials feeder (Model 310, AccuRate, Whitewater, WI).
- Air flow rate: Chamber airflow in the 2-m3 chambers varied between 300 and 370 L/min, depending on the designated exposure concentration.
- Method of particle size determination: The particle size of the aerosols in each exposure chamber was determined weekly using an Andersen Cascade Impactor.
- Treatment of exhaust air: The chamber exhaust air was drawn through a filtering system before being discharged to the outside environment.

TEST ATMOSPHERE
- Brief description of analytical method used: Test article aerosol concentrations were determined both gravimetrically and spectrophotometrically.
Test article exposure concentrations were also monitored weekly using a Perkin-Elmer Lambda 5 UVIVIS Spectrophotometer operated at 334.0 nm. Sampling filters were extracted with 6 ml of HPLC/Spectro Grade Methanol and the optical density of the extract determined.
- Samples taken from breathing zone: yes

VEHICLE (if applicable)
- Concentration of test material in vehicle: 1.0, 5.0 and 10.0 mg/m3

No additional data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dimethyl-2,6-Naphthalene Dicarboxylate aerosol concentrations were determined both gravimetrically and spectrophotometrically. Samples were collected by drawing a given volume of test atmosphere (i.e. approximately 100-200, 250-350 and 800-1000 liters for the high, medium, and low concentration chambers, respectively, and 800-1000 liters for the filtered air control chamber) across an open-faced filter.
Dimethyl-2,6-Naphthalene Dicarboxylate exposure concentrations were also monitored weekly using a Perkin-Elmer Lambda 5 UVIVIS Spectrophotometer operated at 334.0 nm. Sampling filters were extracted with 6 mL of HPLC/Spectro Grade Methanol and the optical density of the extract determined.
Duration of treatment / exposure:
The duration of the exposures was 6 hours per day, 5 days per week, for a total of 20 exposures within a 28-day period.
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1.0, 5.0 and 10.0 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
099, 4.65 and 10.02 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
10 rat/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
None stated
Positive control:
None stated

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The rats were observed once daily for morbidity and mortality during the quarantine period. Following treatment initiation, all rats were observed at least once daily, 7 days/week.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A complete physical examination was performed once prior to study initiation. Clinical observations were performed daily on weekdays during the exposure phase of the study.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were measured at the initiation of the study, weekly during the exposure phase of the study, and at the termination of the study immediately prior to sacrifice.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

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: No data

HAEMATOLOGY: Yes
- Anaesthetic used for blood collection: No data
- Animals fasted: No data

CLINICAL CHEMISTRY: Yes
- Animals fasted: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

No additional data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Necropsies were performed on all rats and the following tissues were collected and fixed in 10% neutral buffered formalin: adrenals, brain, epididymides, eyes, esophagus, femur and bone marrow (smear), gonads, heart, duodenum, Jejunum, Ileum, cecum, colon, kidneys, liver, lungs, lymph nodes (mandibular, respiratory, and mesenteric), mammary gland, nasal turbinates, pancreas, parathyroids, pituitary, prostate and seminal vesicles, salivary glands, sciatic nerve, skeletal muscle, skin, spinal cord, spleen, stomach, thymus, thyroids, tongue, trachea, urinary bladder, uterus, ear with attached tag
HISTOPATHOLOGY: Yes. Any tissue masses or suspect lesions and the lymph nodes which drain the region of the mass or lesion.
Other examinations:
None stated
Statistics:
Means and standard deviations (SD) were calculated for all quantitative parameters.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
The Incidences of salivation and redness around the nose were slightly increased in the Dimethyl-2,6-Naphthalene Dicarboxylate-exposed groups compared to the controls. No rats died during the study.

BODY WEIGHT AND WEIGHT GAIN
There were no statistically significant effects of treatment on body weight or body weight gain during the study.

HAEMATOLOGY
There were no statistically significant effects of treatment on hematology.

CLINICAL CHEMISTRY
There were no statistically significant effects of treatment on the clinical chemistry.

ORGAN WEIGHTS
There were no statistically significant effects of treatment on absolute or relative organ weights or lung volumes.

GROSS PATHOLOGY
Prominent signs observed at necropsy Included lung foci and enlarged, focally reddened mandibular lymph nodes. However, there was no difference in Incidence of these observations between the exposed and the control groups so they were not considered to be treatment-related. Other observations were of a minor, incidental nature.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related microscopic lesions was observed in the nasal turbinates, trachea or lungs of any of the rats exposed to Dimethyl-2,6-Naphthalene Dicarboxylate. The most common microscopic lesions seen included lymphoid and plasma cell hyperplasla in the mandibular lymph nodes, but these were of similar incidence among the exposed and control rats, so that the lesions were not considered to be treatment-related. Other lesions in the exposed rats were minor and of an Incidental nature, unrelated to treatment.

No additional data

Effect levels

Dose descriptor:
NOAEC
Effect level:
10.02 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In an OECD 412 28-day repeated dose inhalation toxicity study in Sprague-Dawley male and female rats, conducted according to GLP, the NOAEC of NDC is 10.02 mg/m3.

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