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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to O.E.C.D. Testing Guideline 412 with GLP compliance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
As per IUCLID Sections 1.1. - 1.4.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Sprague-Dawley rats were acquired from Charles River (UK) Limited Maragate, Kent. The animals were approximately five weeks old and weighted 116 - 134 grams. Animals were acclimated nine days before being placed on study. The animals room coditions were 22 C +/- 3 C, 30 - 70% relative hmidity and 15 - 20 air exchanges per hour. The rats were housed individually in polycarbonate cages containing wood shaveings with stainless steel removal tops and bottoms. Rat and Mouse (Modified) No. 1 Diet SQC Expanded was acquired from Special Diet Services, Stepfield, Witham, Essex. Water was domestic mains quality water. Both feed and water were available ad libitum.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The test chamber atmospheres were generated by a vapourizing system. A test material reserviour was placed in water bath at approximately 60 C and through witch compressed air was passed at a fixed rate. The resulting test substance vapour was then ducted into the inhalation chambers. The various chamber dose levels were achieved by varying the air flow through the test substance reservior and diluting with air as needed. The inhalation chambers were cylindrical stainless steel flow-pass design with a volume of 4.0 liters. Chamber air flow rate was measured continuously and recorede every 30 minutes.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The chamber sampling employeed two glass impingher tubes in series. The sampling devices was temporarily sealed in a port in the inhalation chambers st the animal breathing zone. Air samples were analyzed by a Gas Chromatography method supplied by the study sponsor.
Duration of treatment / exposure:
28 d
Frequency of treatment:
6 h/d
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.06 mg/l
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0.25 mg/l
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
1.43 mg/l
Basis:
analytical conc.
No. of animals per sex per dose:
8
Control animals:
yes, sham-exposed
Details on study design:
The animals were exposed nose-only to vapours of vinyl neononanoate 6 hr/day for 28 consecutive days. Five animals/sex were subjected to a Functional Observational Battery (FOB) once pre-study once weekly during the 28-day exposure period. Clinical signs, body weights and feed consumptions were taken diring the in-life phase of the study. At study termination a variety of standard end-points were observed and/or measured. At study termination satellite groups of three rats/sex subjected to whole body perfusion with paraformaldehyde/glutaraldehyde to fix neural tisse.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
FOB with grip strength and motor activity weekly, Clinical Signs daily, Body Weight and Feed consumption, weekly, blood samples for clinical chemistry measurments and hematology were collected at study termination.
Sacrifice and pathology:
At study termination the main study animals were sacrificed by carbon dioxide ashyxiation. The satellite animals were sacrificed by sublethal injection of sodium pentobarbitone followed by whole body perfusion with paraformaldehyde/gluaraldehyde. The necropsy was directed by a veterinary pathologist. A complete internal and extenal examination was conducted. The weights of protocol speciified organs were taken. Tissues taken from main study animals were fixed in 10% neutral bufferd formailn except eyes were fixed in Davidson's solution and the testis were fixed in Bouin's fluid. Following whole body perfusion peripheral nerve tissue was processed to metyacrylate resin blocks. Tissues from all control and high dose animals were histologically examined. Kidney sections from all low and mid-dose animals were also examined. Haematoxylin and eosin was generally for tissue staining.
Statistics:
Homogeneity of variance using the "F-max" test was generally for detemining statstical significance. Other stastical models were used as needed.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
High dose male animals had significantly reduced mean body weight (33%) at study termination. High dose male feed consumption was significantly reduced 13% at 28 days. Significantly lower plasma urea values were observed for both male and female high dose group animals. High dose female rat group mean liver weight was significantly elevated 16% relative to the control value. Histopathological evidence of adverse kidney effects were observed at all dose levels in male rats. These findings inclued: mild hyaline droplet formation, karyomegally and single cell necrosis.

Effect levels

Dose descriptor:
NOEL
Effect level:
0.25 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Significantly reduced body weight (33%) males only, clinical signs suggestive of neurtoxicity, reduced plasma urea in both sexes and histological evidence of kidney damage, males only at the high concentration of 1.43 mg/L (190 ppm).

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Daily exposure, via the nose only inhalation route to 1.43 mg/l VeoVa9 for 28 days produced treatment-related clinical signs, reduced bodyweight and food intake and reduced plasma urea. Histologically, treatment at this level produced hyaline droplets in the renal cortex and in some rats produced karyomegaly in both the renal cortex and outert stripe of the renal medulla assopciated with single cell necrosis. Since the only changes of note observed in the Low and Intermediate dose animals were related to hyaline droplet formulation and minor renal changes and since these effects are known to be sex and species selective and unlikely to be relevant to man, the no adverse effect level in this study is considered to be 0.25 mg/L (33.2 ppm).
Executive summary:

Rats were exposed nose-only to vapours of vinyl neononaoate in a GLP, O.E.C.D. 412 Testing Guideline 28 -day repeated dose study with neurtoxicity screen. Primary findings of adverse effects occured in male rats at the high dose level of 1.43 mg/L (190 ppm). These cosisted of: a significant 33% reduction in group mean body weight, a significant 13% reduction in feed consumption, signficantly reduced plasma urea and histopathological evidence of adverse kidney effects. The histological evidence of male rat nephrotoxicity is believed to be due to the accumulation of alpha-2u-microglobin that is a mechcanism not relevant ot human health. Therefore, the NOAEL for this study is the mid-dose of 0.25 mg/l (33.2 ppm). This study's results can be used to assist in the development of Worker and General Population inhalation DNELs.