Trifluoroacetyl chloride

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study report was not finalized. Only a draft report is available

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Trifluoroacetyl chloride

EC Number:

206-556-2

EC Name:

Trifluoroacetyl chloride

Cas Number:

354-32-5

Molecular formula:

C2ClF3O

IUPAC Name:

trifluoroacetyl chloride

Details on test material:

name: trifluoroacetylchloride
presentation: liquefied gas
batch number: KF 182701.D

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were inspected for signs of illness at the beginning of the acclimatization period. No abnormalities were detected.
73 male and 73 female rats were used. Except during their stay in the exposure chamber the animals had free access to food and water. Animal room condition: 17.5-24°C, 23-78% relative humidity, 12 hour light/12 hour dark, ventilation frequency 12-15 times/hour, hygienic procedures according to standart operating procedure.

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure:

nose/head only

Vehicle:

other: dry nitrogen

Remarks on MMAD:

MMAD / GSD: no data

Details on inhalation exposure:

no data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The principal method of analysis was adapted from a published method for the analysis of chloroacetyl chloride. A known volume of the atmosphere from the exposure chambers was drawn through glass absorption tubes containing a sampling substrate coated ith 9-[(N-methylamino)methyl]anthracene (MAMA). TFAC reacts with MAMA to form the stable product N-(9-anthracenylmethyl)-2,2,2-trifluoro-N-methylacetamide (MAMA-TFA).

The analysed chamber concentrations of TFAC are presented in two formats:
- Data (in microg/l) based on the absolute amount of MAMA-TFA found by HPLC and the volume of air sampled.
- Data (in ppm) corrected for the efficiency of conversion of TFAC to extractable MAMA-TFA by multiplying the tube recovery results by a factor (0.6068)

Duration of treatment / exposure:

The rats were repeatedly exposed to the test substance (TFAC), for a period of 6 hours each day on 5 consecutive days each week, over a period of 13 weeks.

Frequency of treatment:

The rats were repeatedly exposed to the test substance (TFAC), for a period of 6 hours each day on 5 consecutive days each week, over a period of 13 weeks.

Doses / concentrations

Remarks:

Doses / Concentrations:
0.10 , 0.48 and 1.99 ppm
Basis:
analytical conc.

No. of animals per sex per dose:

10 male and 10 female rats for each dose and as control.

Control animals:

yes, concurrent no treatment

Details on study design:

Control rats received air only.

Positive control:

there is not positive control.

Examinations

Observations and examinations performed and frequency:

- Clinical signs: All signs of ill health, together with any behavioural change or response to treatment, were recorded for each animal individually, during all study period.
- Mortality and morbidity: further checks were made early in each working day and again in the afternoon to look for dead or moribund animals.
- Bodyweight: the weight of each rat was recorded daily beginning 1 week before the start of exposures. during the treatment period, the bodyweights were recorded before exposure on the day.
- Food consumption: the quantity of food consumed by each main study rat was recorded weekly, commencing 1 week before the start of dosing.
- Ophthalmoscopy examination: the eyes of all rats were examined once before the start of exposures and at week 13, using a Keeler indirect ophthalmoscope.

Sacrifice and pathology:

- Sacrifice: following 13 weeks of exposure all rats were killed on the Monday and Tuesday following the last exposure in week 13 (Friday). The rats were killed by intraperitoneal injection of pentobarbitone sodium and exsanguinated from the brachial blood vessels.
- Pathology: A detailed post mortem macroscopic examination of main study rats was performed. The following organs were dissected from each rats and weighted: adrenals, brain, epididymides, heart, liver, lungs, kindneys, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thymus, uterus.
- Bone marrow: necropsy of samples of bone marrow from the tibia were performed.
- Tissue preservation: samples of organs/tissues were preserved and microscopic pathology was performed.
- Immunohistochemistry: Tissues from the respiratory tract were collected to performed immunohistochemical analysis for the determination of TFA-protein complexes.

Other examinations:

Laboratory investigations:
-Sample collection: blood and urine samples were collected from all main stydy animals during week 13 of exposure. The haematological, blood biochemical and urinalysis investigations were performed for each animals.

Statistics:

All statistical analysis were conducted separately for male and female rats. For all parameters, the analyses were carried out using the individual animal as the basic experimental unit.
Bodyweight data were analysed using weight gain. Food consuption data were analysed using cumulative cage totals.
The following sequence of statistical tests was used for bodyweight, clinical pathology and organ weight data:
If the data consisted predominantly of one particular value, the proportion of animals with values different from the mode was analysied by appropriate methods. Otherwise:
-Bartlett's test was applied to test for heterogeneity of variance between treatments.
-Analysis of variance was followed by Student's test and Williams' test for a dose-related response although only Williams' test was reported. The Kruskal-Wallis analysis were followed by the non-parametric equivalents of the "t" test and Williams' test.

Additionally, for organ weight data, analysis of covriance was carried out adjusting for the final bodyweight where the regression coefficient describing the linear relationship between organ weight and the covariate was significantly different from zzero at the 10% level. Where there was no such relationship, analysis of variance was performed on the unadjusted values. Significance testing was performed at 5% and 1% levels.

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):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis 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:

There were no unscheduled deaths during the study.
There were no clinical signs indicative of a toxic or irritant effect attributable to exposure to TFAC.
Overall mean bodyweight gains and cumulative food consumption were similar to control values.
Investigation of haematology parameters revealed a lower mean platelet volume (MPV) for high and intermediate dose males and all female TFAC-teated groups. A higher platelet distribution width (PDW) was also noted for all groups (both sexes) exposed to TFAC. The toxicological significance of the apparent shift ion the platelet size is not known.
Blood biochemistry and urinalysis parameters investigated in Week 13 were unaffected by exposure to TFAC.
There was no treatment-related findings noted macroscopically at necropsy.
The microscopic pathological examination revealed changes in the lungs and tracheobronchial lymph nodes at the high and low exposure levels only. At the high dose level macrophage aggregation and inflammation were seen in the alveolar ducts, moderate perivascular lymphoid aggregates peribronchiolar lymphoid infiltration and/or prominent germinal centres were seen. In addition, prominent germinal centres and/or medullary plasmacytosis were seen in the tracheobronchial lymph nodes of rats exposed at low dose level.

Effect levels

Dose descriptor:

NOAEC

Effect level:

< 0.1 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Mortality and clinical signs: No mortality observed during the study. No clinical signs indicative of toxic or irritating responses were observed.

Bodyweights were not affected by the exposure to TFAC

No changes were observed in blood chemistry and urinalysis

Haematology showed a lower mean platelet volume at high and mid concentration males and in all female groups. Moreover, a higher platelet distribution width was also observed in both sexes from all treatment groups. The changes in platelet size were considered of doubful toxicological significance.

Organ weight: a small increase in lung weight was observed in the high concentration group.

Histopathology: macrophage aggregates, alveolar duct inflammation and perivascular lymphoid aggregates were observed at the high dose level. Granulomatous inflammation, perivascular lymphoid aggregations and peribronchiolar lymphoid infiltration and/or prominent germinal centres were detected at the low concentration level.

No treatment-related changes were observed at the intermediate concentration.

Applicant's summary and conclusion

Conclusions:

Exposure of rats over a 90-day period to the vapour of TFAC at 2 ppm caused a mild inflammatory response in the lungs consistent with the corrosive nature of this material. Signs of inflammation of similar severity were observed also at the lowest tested concentration, 0.1 ppm, but not at the mid concentration (0.48 ppm). This behaviour was tentatively related by the study director to the ability of TFAC to act as a hapten. The study director speculated that TFAC could mainly act as a hapten at the lowest concentration, whereas the corrosive properties could play a role in the inflammatory response observed at the highest concentration. However this interpretation can hardly explain the total absence of inflammatory changes observed at the mid concentration.

Exposure of rats over a 90-day period to vapour of TFAC at 0.1 ppm caused a predominantly lymphocytic local response in the lungs and local lymph nodes which may represent a reaction by the immune system not induced at higher exposure levels. Although there was no effect at 0.5 ppm, a no effect level was not established in this study because exposure at 0.1 ppm elicited an apparent immune response.

Executive summary:

The sub-chronic toxicity of TFAC was studied in a 90-day inhalation toxicity study in Sprague-Dawley rats. The animals (10/sex/dose) were exposed to 0, 0.1, 0.5 and 2 ppm TFAC for 13 weeks (6 h/day, 5 days/week). Clinical signs, food and water consumption, changes in body weight were recorded daily during the study period; ocular examination was performed before the exposure period and on the last day of exposure. Blood and urine samples were collected on week 13 for the performance of clinical chemistry, hematology and urine analyses. Organ weight, gross and microscopic pathology examinations were performed at the end of the exposure period.
No mortality or clinical signs indicating irritating responses were observed during the exposure period. No changes were observed in bodyweights and food consumption. Hematology showed a slight but statistically significant decrease in mean platelet volume (in males at ≥ 0.5 ppm and in females at all tested concentrations) and in platelet distribution width (in both sexes at all tested concentrations). Lymphocyte and basophile counts were statistically significantly lower in males at ≥ 0.5 ppm, resulting in a lower white blood cell count observed in those concentrations in comparison to control. Although statistical relevance was achieved, those changes were not dose-related. An increased lung relative weight was observed in females and males exposed to 2 ppm (statistical relevance attained in females only). The histopathological examinations revealed an increased incidence of macrophage aggregates, alveolar duct inflammation and perivascular lymphoid aggregates in both sexes exposed to the highest concentration (2 ppm). Similarly, increased incidence of perivascular lymphoid aggregation was observed in both sexes of the low exposure concentration group, but not in the mid exposure concentration group in comparison to control. Furthermore other changes related to inflammatory responses in the lung (alveolar duct granulomatous inflammation), bronchus (BALT-prominent germinal centres and peribronchiolar lymphoid infiltration) and tracheobronchial lymph nodes (prominent germinal centres and protomedullary plasmacytosis) were observed in the low exposure concentration group only.
Due to the results of the histopathological examinations, no NOAEC could be assigned to this study. It should be noted that the study has not been finalized and only a draft report is available.