Alkenes, C6-11 (branched), hydroformylation products, distn. residues, heavy cracked fraction

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Summary from a publically available document.

Data source

Reference

Reference Type:

other: Grey literature

Title:

Alkenes, C6-10, hydroformylation products, high boiling.

Author:

BASF Corporation

Year:

2003

Bibliographic source:

U.S. EPA HPV Challenge Program Submission

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Alkenes, C6-10, hydroformylation products, high-boiling

EC Number:

271-230-9

EC Name:

Alkenes, C6-10, hydroformylation products, high-boiling

Cas Number:

68526-82-9

Molecular formula:

None available

IUPAC Name:

None available - not a single isomer - see remarks

Details on test material:

- Name of test material (as cited in study report): Alkenes, C6-10, hydroformylation products, high-boiling

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Chambers were one cubic meter steel and glass operated dynamically at calibrated initial airflows between 199 and 218 liters per min. Aerosol was generated from the neat test material using a Laskin nebulizer at backpressures of 5, 8, or 15 psi for low, mid and high dose groups respectively.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

not specified

Remarks on MMAD:

MMAD / GSD: MMAD of 1.6, 1.4 or 1.6 microns for low, mid and high dose groups, respectively with 100% of the particles less than 10 micron.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 hours per day

Frequency of treatment:

5 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/m3
Basis:
no data

No. of animals per sex per dose:

no data

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

Opthalmoscopic examinations were conducted prior to the start of treatment and at the end of the study. Blood was obtained from 10 rats/group for evaluation before the study, after about one month of treatment, and at the end of the study. The specific parameters evaluated are listed below. A complete necropsy was performed on all animals that died on test, or were sacrificed at study termination.

Results and discussion

Effect levels

Dose descriptor:

NOEC

Effect level:

100 mg/m³ air (nominal)

Based on:

not specified

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

One mid-dose female was accidentally killed during the interim blood sample collection and one high-dose male and two high-dose females died during the study. The high-dose group deaths were considered treatment related. An increased incidence of nasal discharge and rough coats were observed in rats from the mid- and high-dose groups. No treatment related opthalmoscopic findings were present.

 

Body weights gains were slightly reduced in high-dose rats by about 8% throughout the study. This reduction was statistically significant only for females.

 

Few statistically significant hematological and clinical chemistry changes were observed and there was no pattern consistent with a treatment related effect; therefore, the following changes were not considered as toxicologically significant. High-dose males at interim sacrifice showed increased erythrocyte counts and serum phosphorus. High-dose males at terminal sacrifice showed increased BUN and decreased triglycerides.

 

Organ weights: Relative and absolute lung weights were increased for mid-dose males and rats of each sex in the high-dose group. This was associated with an increased incidence of intra-alveolar accumulation of macrophages and considered treatment related. Other changes in organ weights were observed for the mean relative weights of kidneys, adrenals and liver in the high-dose females. None of these were associated with evidence of organ damage or clinical-chemistry associated findings and were, thus, not considered toxicologically significant.

 

Pathology: A cytoplasmic accumulation of eosinophilic material, ranging from minimal to moderate in severity, was observed in the respiratory epithelial cells of almost all treated rats and a small number of control rats. The severity of this finding indicated a dose response relationship. Treated rats, but not controls, showed minimal to moderately severe necrosis of the respiratory-epithelium that was accompanied by an accumulation of eosinophilic particulate material on the luminal surface of the mucosa.

 

High-dose group animals showed subacute to chronic interstitial inflammation of mild to moderate severity. An increased intra-alveolar accumulation of macrophages was observed in the lungs of rats from the mid- and high-dose groups. Focal accumulation of foamy macrophages, which ranged in severity from minimal to moderate, was observed in treated rats. Other gross and microscopic changes, which were observed, either occurred in the treated and control rats or they occurred spontaneously.

No changes attributed to treatment in any organ system related to reproductive function were mentioned in the laboratory report although most reproductive organs from high dose and control animals underwent macroscopic and microscopic evaluation.

Applicant's summary and conclusion

Executive summary:

A subchronic aerosol inhalation study of CAS# 68526 -82 -6 was conducted in 1987 (24). Groups of 15 Sprague-Dawley rats of each sex were exposed to atmospheres containing the test substance six hours a day, five days a week for 13 weeks. The target levels of test substance were 0, 100, 300, and 1000 mg/m3 and the achieved concentrations were very near target levels. Clear treatment related effects were observed in rats from the high-dose group manifest as reduced body weight gains, increased lung weights and microscopic pulmonary morphology. Mid-dose group animals exhibited an increase in lung weigh only for males and microscopic effects that were considered by the examining pathologist to be indicative of a “physiological response to aerosol exposure” and of questionable toxicological significance. In light of the dose-response continuum and minimal microscopic effects at the low dose, the mid dose is considered a LOAEC and the low dose is considered a NOAEC. The only target organ identified was the respiratory tract where necrosis of olfactory-respiratory epithelium was observed in numerous treated animals but not in controls. Additionally, mid and high-dose animals showed interstitial inflammation of the lungs in rats. No changes attributed to treatment in any organ system related to reproductive function were mentioned in the laboratory report although most reproductive organs from high dose and control animals underwent macroscopic and microscopic evaluation.