Distillates (Fischer-Tropsch), C8-10-branched and linear

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions. Only male rats were used; no organs were weighed and there was no recovery period.

Data source

Reference

Reference Type:

publication

Title:

Petroleum hydrocarbon toxicity studies II. Animal and human response to vapours of varnish makers and painters naphtha

Author:

Carpenter, C. et al.

Year:

1975

Bibliographic source:

Toxicology and Applied Pharmacology 32: 263-281

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

- Only male rats were used; no organs were weighed and there was no recovery period.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hydrocarbons, C7-C9, n-alkanes, isoalkanes, cyclics

EC Number:

920-750-0

IUPAC Name:

Hydrocarbons, C7-C9, n-alkanes, isoalkanes, cyclics

Details on test material:

- Name of test material (as cited in study report): VM&P naphtha
- Physical state: vapour
- Analytical purity: 100% pure commercial product
- Composition of test material, percentage of components: 55% paraffins, 33% cycloparaffins, 12% alkylbenzene, distributed as 48% light hydrocarbons up to C8, 26% C9, 14% C10 and higher, and 12% aromatics by mass spectrometry

Test animals

Species:

rat

Strain:

other: Albino Harlan-Wistar

Sex:

male

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: not applicable

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4 L inhalation chamber

VM&P naphtha was wholly vaporised by passage through an electrically heated vertical Pyrex tube containing a spiral groove wound with Ni-chrome wire. Resultant vapours were carried into the inhalation chamber by a counter current air stream. Desired concentrations were produced by controlling the amount of liquid vaporised into the metered air. The evaporator was designed so that mixtures were unchanged by overheating and vapour composition matched liquid composition. All chambers were operated under negative pressure. Chamber air samples, collected with airtight syringes were injected within 30 sec. after capture into a gas chromatograph; samples were taken twice a day.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysed by gas chromatography

Duration of treatment / exposure:

13 weeks (65 exposure days)

Frequency of treatment:

6 hours/day
5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 2, 4, 8 mg/L
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 1.3, 2.8, 5.8 mg/L (corresponding to 0, 280, 600, 1200 ppm)
Basis:
analytical conc.

No. of animals per sex per dose:

25

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- overall appearance and behavior was checked daily.


DETAILED CLINICAL OBSERVATIONS: Yes
- overall appearance and behavior was checked daily.


BODY WEIGHT: Yes
- daily during the first week of exposure and weekly thereafter


HAEMATOLOGY: Yes
- All blood was collected from cervical vessels. Hematology included hematocrit, total erythrocyte counts, reticulocyte counts, total and differential leukocyte counts.


CLINICAL CHEMISTRY: Yes
- Parameters were serum alkaline phosphatase, SGOT, SGPT, and blood urea nitrogen.


URINALYSIS: Yes
- Urinalysis was performed on 3, 3, and 4 rats/group prior to sacrifice at weeks 3, 8 and 13 weeks, respectively.

OTHER:
Clinical pathology was performed on 3, 3, and 4 rats/group prior to sacrifice at weeks 3, 8 and 13 weeks, respectively.
Reproductive organs were not examined.

Sacrifice and pathology:

3 rats from each group were sacrificed for histopathologic evaluation after 3 and 8 weeks (15 and 40 actual exposure days, respectively) and all surviving rats at week 13, after 65 days of exposure.
GROSS PATHOLOGY: Yes
- Gross necropsies were performed on all rats but no organs were weighed.
HISTOPATHOLOGY: Yes
- Histopathology was performed on brain, heart, trachea, thyroid, parathyroid, liver, lung, kidney, adrenal, pituitary, spleen, duodenum, ilium, jejunum, colon, pancreas, skeletal muscle, bone marrow and sciatic nerve.

Statistics:

Results of quantitative continuous variables (e.g. body wt changes) were evaluated using Bartlett's homogeneity of variance, analysis of variance and rank sum. Duncan's multiple range test was used if F for ANOVA was significantly high. If Bartlett's test indicated heterogeneous variances, the F-test was used for each group versus controls. If these F tests were not significant, Student's t-test was used; if significant, means were compared by Cochran t-test or rank sum test. Frequency data (e.g. mortality, micropathological conditions) were compared between groups by Chi-square with Yates correction for continuity. Critical level of significance was 0.05.

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):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
Toxic response/effects by dose level: Mortality: 2 rats in the 1.3 mg/L group died of lung abscesses and peumonia on the 9th and 65th days of exposure. These were the only deaths during the study and as these occurred at the lowest dose level only, they were considered not to be treatment-related.


BODY WEIGHT AND WEIGHT GAIN
No statistically significant (t = 0.67) variations between controls and any treated group were observed for body weight changes.


HAEMATOLOGY
5.8 mg/L group: Statistically significant increases (0.05 > p > 0.01) in neutrophils and decreased leukocyte counts were observed in rats sacrificed after 8 weeks. These effects were within normal range and were not seen in rats at 13 weeks, however a statistically significant decrease (0.05 > p > 0.01) in erythrocyte counts did occur.

CLINICAL CHEMISTRY
No statistically significant variations between controls and any treated group were observed for clinical chemistry.


GROSS PATHOLOGY
Some tubular regeneration in the kidneys of all rats (control and treated groups) was observed but was not progressive with concentration or duration of exposure to VM&P naphtha and was not considered of biological significance.

OTHER:
For animals exposed to the challenge dose of 27 mg/L, treated rats at 2.8 and 5.8 mg/L were more resistant in terms of mortality than concurrent controls or naive, untreated rats. The 2.8 mg/L rats demonstrated a statistically significant (p > 0.05) increase in "time to death".
The 1.3 mg/L group was comparable to controls.

Effect levels

Dose descriptor:

NOAEC

Effect level:

5 800 mg/m³ air (analytical)

Sex:

male

Basis for effect level:

other: haematology: statistically significant decrease in erythrocyte counts

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Statistically significant increases in neutrophils and decreased leukocyte counts were observed in rats sacrificed after 8 weeks. These effects were within normal range and were not seen in rats at 13 weeks, however a statistically significant decrease in erythrocyte counts did occur. Therefore a NOAEC of 5.8 mg/L air (analytical concentration) was determined.

Executive summary:

Statistically significant increases in neutrophils and decreased leukocyte counts were observed in rats sacrificed after 8 weeks. These effects were within normal range and were not seen in rats at 13 weeks, however a statistically significant decrease in erythrocyte counts did occur. Therefore a NOAEC of 5.8 mg/L air (analytical concentration) was determined.