Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1982-07-20
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was classified as reliable without restriction because it was a well-documented study and followed OECD Guideline 413. Read-across is considered to be scientifically valid and reliability 2.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no data reported on the age or fasting of the animals; calibration of exposure analyzers assumed chemical was 100% pure; lacked description of the control group and dose selection; and food consumption.
GLP compliance:
yes (incl. certificate)
Remarks:
International Research and Development corporation Quality Assurance Department
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): n-butyl mercaptan (butane-1-thiol)
- Substance type: clear, colourless
- Physical state: liquid
- Analytical purity: 97.5 weight %
- Lot/batch No.: 601-NB-80
- Expiration date of the lot/batch: Shelf life was reported as 'In excess of one year.' Test material was received from Penwalt May 20, 1980.
- Storage condition of test material: normal indoor ambient conditions
- Other: IRDC: 7036

Test animals

Species:
rat
Strain:
other: Charles River CD (albino)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Weight at study initiation: 200 to 270 grams
- Housing: caged individually
- Diet (e.g. ad libitum): Purina Certified Pelleted Rodent Chow ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: four days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 to 29.4°C
- Humidity (%): 28 to 68
- Photoperiod (hrs dark / hrs light): 12 hours


IN-LIFE DATES: From: 1981-03-23 To: 1981-06-19

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m3 glass and stainless steel chamber
- Source and rate of air: HVAC system, rate varied between 130 and 300 litres/minute depending on desired exposure concentrations
- Method of conditioning air: particulate filtered and controlled for temperature and humidity
- System of generating particulates/aerosols: pump or Sage Syringe Drive delivers test material to the top of the glass bead column, air is passed up the bead column in a counter-current manner relative to the liquid, vaporisation occurs within the bead column, vapours are piped to exposure chamber air outlet where dilution with chamber ventilation air reduces the concentration to the desired level.
- Temperature, humidity, pressure in air chamber:
- Air flow rate: rate varied between 130 and 300 litres/minute depending on desired exposure concentrations


TEST ATMOSPHERE
- Brief description of analytical method used: Nominal concentrations were calculated by recording the weight of test material contained in each syringe or reservoir prior to and after each exposure. The calculated difference was divided by the total volume of air passed through the chamber during each exposure to determine the nominal concentration.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Actual exposure concentrations were measured by non-dispersive IR utilising analysers. Analyzers were prime calibrated once before initiation of the study and then at monthly intervals. Calibrations were performed in triplicate, responses were averaged and plotted, and a linear least-squares fit was applied. Exposure was monitored at approximately hourly intervals and from this the mean and standard deviation was determined.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.03, 0.26, 0.55 mg/L (33, 260, 550 mg/m3)
Basis:
nominal conc.
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
Details on study design:
No data reported
Positive control:
No data reported

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once per week
- Cage side observations checked in table [No. 6 for week thirteen] were included.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to exposure, 6 weeks, and 12 weeks


BODY WEIGHT: Yes
- Time schedule for examinations: once per week


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to exposure, 6 weeks, and 12 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10
- Parameters checked in Appendix C were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to exposure, 6 weeks, and 12 weeks
- Animals fasted: No data reported
- How many animals: 10
- Parameters checked in appendix D were examined.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
No data reported
Statistics:
Generally, when the number of animals in any one group was equal-to-or-less-than seven, non-parametric analyses were conducted utilizing the Kruskal-Wallis one-way analysis of variance followed, where appropriate, with the Mann-Whitney. In those cases where the number of animals in all groups was greater than seven and the measurements were at least on an internal scale (continuous data) parametric analyses were conducted utilizing Bartlett’s Chi-square test for homogeneity of variance, followed where appropriate, by an analysis of variance and then where appropriate by Dunnett’s t. In all cases the level of rejection was at the five percent level.

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 specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY Animals displayed no pharmacotoxic signs that were considered to be exposure-related. Two animals died during the course of the study, a male in Group IV and a female in Group III. The cause of death for the female is unknown. The death of the male may have been related to blood collection trauma, as it died shortly after blood collection.

BODY WEIGHT AND WEIGHT GAIN There were no statistically significant exposure-related effects on body weight in males or females. It appears that there could be some dose-response effect on body weight in males with respect to test materials, but this observation was not as apparent in female rats. Therefore, the apparent dose-response trends are not considered to be of toxicological importance.

FOOD CONSUMPTION
No data reported

FOOD EFFICIENCY
No data reported

WATER CONSUMPTION
No data reported

OPHTHALMOSCOPIC EXAMINATION
No data reported

HAEMATOLOGY There were no significant differences observed between any of the groups for any of the hematology parameters at the pre-initiation interval. There is only one parameter for which a significant difference was observed for the individual 6-week hematology values. The erythrocyte count was decreased in female rats of Group IV when compared to the female control group. The values obtained are not considered to be outside a "normal" range and are not considered to be of biological significance. The individual 12-week hematology values had three parameters for which statistically significant differences for females of various exposure groups were found when evaluated against female control animals: Group IV had a high segmented neutrophil count, the erythrocyte counts for Groups III and IV were low and the lymphocyte count for Group IV was significantly lower. The observed statistical significant differences obtained for erythrocyte count, lymphocytes, and segmented neutrophils for Group IV are not considered to be of toxicologic importance.


CLINICAL CHEMISTRY There were no significant differences observed between any of the groups for any of the clinical chemistry parameters at the pre-initiation interval or the 12 week interval. The only parameter for which a statistically significant difference was observed was for the slightly elevated BUNN of Group IV males. Due to the fact that this was a singular occurrence and that the value is still within the "normal" range, this difference is probably not biologically important.

URINALYSIS
No data reported

NEUROBEHAVIOUR
No data reported

ORGAN WEIGHTS Absolute lung and trachea weight for Group III males and relative lung and trachea weight for Groups III and IV males was statistically significantly different from the control group. No such effects were observed in the females exposed to the same test material. These effects may be related to the n-butyl mercaptan exposure because the lung is a logical target organ and the effect was observed at both of the higher exposure levels.

GROSS PATHOLOGY Test article-related microscopic changes were observed in lungs of male and female rats from the test material. The lung lesions consisted of interstitial fibrosis, which involved one or more of all lobes, a diffuse distribution was evident. In the areas of fibroplasia, a minimal number of chronic inflammatory cells, was also present. However, their distribution was sparse, so that the overall picture presented was one of interstitial fibroplasia. Interstitial inflammatory cell infiltrate, composed primarily of chronic inflammatory cells, occurred in the control and test material exposed rats. Young fibroblasts were also seen sparsely distributed in these area. The distribution and incidence of this lesion in control and the exposed rats were indicative of its spontaneous nature and no compound effect was evident with respect to this lesion. Incidental non-treatment-related lesions were observed in adrenal, heart, liver, bronchial and cervical lymph nodes, nasal turbinates, prostate, testes, trachea, eye, stomach, and thymus.

OTHER FINDINGS
MACROSCOPIC PATHOLOGY Two rats died during the study but neither of these animals or any of the animals terminally sacrificed showed any test article related to macroscopic changes.

Effect levels

Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
550 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: No adverse systemic effects observed.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a 90-day inhalation toxicity study, butane-1-thiol was administered to 15 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 0.033, 0.26, or 0.55 mg/L (0, 9, 70, or 150 ppm) for 6 hours per day, 5 days/week for a total of 91 days. Based on this observation, the local NOAEC based on effects on the respiratory tract was 0.033 mg/l (33 mg/m3), but treatment-related systemic toxicity were not observed, so the NOAEC for systemic toxicity is >=0.55 mg/l (550 mg/m3). (Ulrich, 1982).
Executive summary:
In a 90-day inhalation toxicity study, butane-1-thiol was administered to 15 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 0.033, 0.26, or 0.55 mg/L (0, 9, 70, or 150 ppm) for 6 hours per day, 5 days/week for a total of 91 days (Ulrich, 1982).

 

There were no statistically significant compound related effects in appearance and behaviour, mortality, body weight, hematology, clinical chemistry, or macroscopic pathology. Organ weights of the lung and trachea were statistically different form some groups compared to the control, microscopic pathology changes were observed in lungs of male and female rats. Male rats treated with the test material at all test concentrations exhibited exposure related nephrosis of the kidney but this effect was not seen in female rats.  An increased incidence of alveolar macrophages was observed in male and female rats treated with butane-1-thiol at concentrations of 0.26 and 0.55 mg/L. Based on this observation, the local NOAEC based on effects on the respiratory tract was 0.033 mg/l (33 mg/m3), but treatment-related systemic toxicity were not observed, so the NOAEC for systemic toxicity is >=0.55 mg/l (550 mg/m3).

 

This study received a Klimisch score of 2 and was classified as reliable without restriction because it was a well-documented study and followed OECD Guideline 413.