HCFC-22 (chloro-difluoro-methane)

Chlorodifluoromethane is rapidly equilibrated in tissues after inhalation and is eliminated from the blood in expired air with a half life of a few minutes. Over a wide range, the inhalation concentrations and blood concentrations are linearly correlated. Metabolism occurs, if at all, in only minor amounts; the toxicological activities described are unlikely to be due to the formation of reactive intermediates.

Chlorodifluoromethane has an extremely low order of acute toxicity.
Atmospheric concentrations over 700,000 mg/m3 are required to produce a lethal effect.

When liquid chlorodifluoromethane is in contact with skin it causes local freezing. It is not a skin sensitiser.

Chlorodifluoromethane causes cardiac sensitisation when exposure is to concentrations approaching the LCM'.
In animal studies, chlorodifluoromethane showed no adverse effects on fertility. It was not teratogenic in rabbits in a study using conventional group sizes at doses up to

175,000 mg/m3 .In initial teratogenicity studies in rats, litters from treated groups contained a low incidence of litters with foetuses with microphthalmia or anophthalmia. In a very large study in which groups of about 400 pregnant rats were exposed to 175,000 mg/m3, there was a low incidence of anophthalmia and microphthalmia combined (10 foetuses in 383 litters). This increased incidence was statistically significant when compared to concurrent controls; however there was a considerable variation in prospective controls with incidences similar to this high dose group's in studies conducted 6 years later. The concentration used (175,000 mg/m3) is equivalent to approximately 25% of the 4hr LC50 and there was a slight reduction in maternal body weight gain indicating maternal toxicity. It is concluded that these results are not of significance when considering the health of human beings occupationally exposed at or below recommended permissable exposure levels.

Chlorodifluoromethane is not considered to be genotoxic in viva. Most in vitro tests are negative and a positive response in the Ames test is consistent with occurrence of bacteria-specific metabolic pathways.

In studies in which rats and mice were exposed to chlorodifluoromethane for 4 - 131 wks, only minimal effects or no effects were observed. A slight decrease in body weight gain and a small increase in liver and kidney weight occurred with an exposure level of 175,000 mg/m3. The only exception was a limited study in rats, mice and rabbits which reported changes in the blood, liver, lung and nervous system in animals exposed to 49,000 mg/m3 over a ten months period; these findings were not confirmed in subsequent studies.

Chlorodifluoromethane did not produce neoplastic changes in female rats and male and female mice exposed to concentrations as high as 175,000 mg/m3. In one study in male rats, a concentration of 175,000 mg/m3 was associated with an increase in the number of fibrosarcomas and Zymbal gland tumours; these occurred late in the study and are not considered to be relevant to man. Lower concentrations (35,000 mg/m3 and below) did not increase tumour rates in this study or in any of the other studies. Overall the data do not indicate that chlorodifluoromethane constitutes a carcinogenic hazard to man.

Although the material has been used for several decades, reports on adverse health effects in man are rare and are consistent with findings in experimental animals.

Source:
Joint Assessment of Commodity Chemicals No. 9
CHLORODIFLUOROMETHANE (HCFC-22)
ECETOC, October 19, 1989

HCFC-123 (2,2-dichloro-1,1,1- trifluoro-ethane)

Studies in rodents indicate that dichlorotrifluoroethane is easily absorbed via the respiratory route and undergoes a biphasic uptake. It is distributed in all organs and is more concentrated in the liver.
About 90% of unchanged dichlorotrifluoroethane was eliminated via the lungs. The rest was metabolised to trifluoroacetic acid which was excreted in the urine. Small amounts of trifluoroacetylated proteins were detected in exposed rats.

Dichlorotrifluoroethane has a low order of acute toxicity. Its oral approximate lethal dose in rats was 9,000 mg/kg; its 4-hour-inhalation LC50 was 200,000 mg/m³ in rats and 178,000 mg/m³ in hamsters. Its dermal LD50p in rats and rabbits was greater than 2,000 mg/kg. The primary effect was a rapidly reversible central nervous depression. After a few minutes exposure it induced prenarcotic effects at 31,300 mg/m³ and anaesthesia at 129,000 mg/m³ in rats.

Liquid dichlorotrifluoroethane did not induce skin irritation in rabbit or skin sensitization in guinea pigs but it caused moderate eye irritation in rabbits.

Repeated inhalation exposure studies in rats exposed 6 h/d, 5 d/wk, for 4 to 13 weeks, to vapour levels of up to 125,000 mg/m³, have resulted in bodyweight decreases and liver weight increases but with minimal adverse histological findings. Dichlorotrifluoroethane was found to cause a marked drop in serum cholesterol, triglyceride and glucose levels at 1,880 mg/m3 and above. Signs of CNS depressing effects were seen during exposure periods above 6,250 mg/m³. However, there was no evidence of neurotoxicity when specific testing for neurobehavioural and nervous tissue histology were performed in a 13-week neurotoxicity study in rats.

Dichlorotrifluoroethane elicited cardiac sensitization to adrenaline in dogs acutely exposed by inhalation at a concentration of 119,000 mg/m³. The no-effect-level was 62,500 mg/m³.

No clear effects were seen in serum steroid hormone and CCK levels in rats and guinea pigs exposed to dichlorotrifluoroethane. In rats dichlorotrifluoroethane produced minimal decreases in testicular luteinizing hormone and testosterone levels under stimulation conditions only.
Dichlorotrifluoroethane was found to induce liver peroxisome proliferation in rats. Its proliferating potential is weak and may be due to its metabolism to trifluoroacetic acid.

Dichlorotrifluoroethane was not teratogenic or embryotoxic to rats and rabbits exposed by inhalation at concentrations of 31,300 and 62,500 mg/m³ which induced slight maternal toxicity.

In a two-generation inhalation study conducted with dichlorotrifluoroethane in rats exposed 6 h/d, 7 d/wk at concentrations ranging from 188 to 6,250 mg/m³, there were no effects on mating performance and offspring survival. Growth retardation was observed in pups during nursing at all test concentrations, but normal growth was restored in the post-weaning phase.
Dichlorotrifluoethane was inactive in several in vitro studies including a series of Salmonella typhimurium assays, a Saccharomyces cerevisiae assay and a cell transformation assay. It was active only in the human lymphocyte chromosome abberation assay. Dichlorotrifluoroethane was clearly inactive in a series of in viva studies, including mouse micronucleus, rat chromosome abberation and rat unscheduled DNA synthesis. In conclusion, dichlorotrifluoroethane is not genotoxic in viva and therefore does not have toxicologically significant genotoxicity.

Rats were exposed 6 h/d, 5 d/wk for 2 years by inhalation in a lifetime study to concentrations of 1,875; 6,250 and 31,300 mg/m³. Compared to controls, survival was significantly improved in an exposure related pattern in all exposed groups. Significantly depressed bodyweights and levels of serum triglycerides, glucose and cholesterol were observed. Compound-related increased incidences of benign tumours were observed in the liver, testis and pancreas. These tumours were a continuum from hyperplasia and occurred late in life. It is thought that they are related with non-genotoxic mechanisms associated with the peroxisome proliferating potential of dichlorotrifluoroethane or with hormonal disturbances occurring in senescent rats. Considering they occurred late in life and were benign, the relevance of these findings is questionable in terms of a carcinogenic risk to man.

Source:
Joint Assessment of Commodity Chemicals No. 33
HCFC-123 (1,1-Dichloro-2,2,2-Trifluoroethane)
ECETOC, February 1996

HCFC-124 (1 chloro-1,2,2,2-tetrafluoroethane)

In limited studies in rats to evaluate metabolic fate and pharmacokinetics, chlorotetrafluoroethane appears to undergo oxidative metabolism resulting in the excretion of trifluoroacetic acid and fluoride ion in the uriue. Studies to assess the metabolic fate of inhaled tetrafluoroethane in rats, mice, and hamsters are currently in progress.

Chlorotetrafluoroethane has a low order of acute inhalation toxicity with a 4-hour LC in rats between 1,283,400 and 1,674,000 mg/m³ (230,000 and 300,000 ppm). The main toxicological action of this fluorocarbon during exposure is weak anaesthesia. As with many other halocarbons and hydrocarbons, inhalation of high concentrations of chlorotetrafluoroethane, followed by an intravenous epinephrine challenge to simulate stress, can induce a cardiac sensitization response in dogs. In these experimental screening studies, cardiac sensitisation (life-threatening arrhythmia) was seen at concentrations of 146,000 mg/m³ (26,000 ppm) and above. The no-observable-effect-level was 55,800 mg/m³ (10,000 ppm).

In a 2-week inhalation toxicity study, rats exposed to 558,000 mg/m³ (100,000 ppm) chlorotetrafluoroethane showed no adverse effects. In 90-day studies at concentrations as high as 279,000 mg/m³ (50,000 ppm), rats and mice showed minimal toxic effects such as slight central nervous system depression and minor blood chemistry changes. No-observable-effect level in these 90-day studies was 27,900 mg/m³ (5,000 ppm) for male rats whilst for male mice a NOEL was not achievable. For female rats and mice a NOEL of 15,000 ppm was established. A lifetime inhalation toxicity/carcinogenicity study in rats is currently in progress.

No evidence of embryotoxicity or teratogenicity of chlorotetrafluoroethane was seen in developmental studies by inhalation in rats and rabbits at exposure levels as high as
279,000 mg/m³ (50,000 ppm). Minimal evidence of maternal toxicity was seen at concentrations of 83,700 mg/m³ (15,000 ppm) and above in each of these studies.

Chlorotetrafluoroethane was not mutagenic either in in vitro or in in vivo studies using bacteria or yeast or mammalian cell lines or the mouse micronucleus assay.

Source:
Joint Assessment of Commodity Chemicals No. 25
HCFC 124 (1-chloro-1,2,2,2- tetrafluoroethane)
ECETOT 1994

HCFC-141b (1 ,1-dichloro-1-fluoroethane)

Studies in animals indicate that dichlorofluoroethane is easily absorbed via the respiratory route.Minimal metabolism of dichlorofluoroethane to 2,2-dichloro 2-fluoroethanol occurs. This metabolite is excreted in the urine of the rat in the form of its glucuronide conjugate.

Dichlorofluoroethane has a low order of acute toxicity. No mortality was observed in rats receiving oral doses of 5,000 mg/kg; only piloerection was noted. Dermal exposure of rats or rabbits to 2,000 mg/kg caused no mortality and no signs of toxicity.

Single exposure inhalation studies in mice indicate that the LC50 (30 min) was between 300,000 and 500,000 mg/m3 (61,800 ppm and 103,000 ppm respectively) and the LC50 (4h) in rats was 300,700 mg/m3 (62,000 ppm). Six hours exposure caused narcosis in mice at 198,850 mg/m3 (41,000 ppm) and pre-narcotic signs were seen in mice and rats at levels higher than 145,500 mg/m3 (30,000ppm).

Liquid dichlorofluoroethane was not an irritant or a sensitising agent to skin, but may cause mild eye irritation.

No significant respiratory effects were seen in rats exposed to 48,500 mg/m3 (10,000 ppm) dichlorofluoroethane for 25 minutes but at this concentration cardiac sensitisation to adrenaline could be induced in dogs and monkeys.

In repeated inhalation exposure studies, rats exposed 6 h/d, 5 d/wk, during periods ranging from 2 to 13 weeks the no-effect-level was considered to be 38,400 mg/m3 (7,900 ppm). Concentration of 97,000 mg/m3 (20,000 ppm) induced reduced alertness, reduced bodyweight gain and slightly increased levels of cholesterol, triglyceride and glucose.

No haematological and histopathological changes were noted.

There was no evidence of teratogenic or embryotoxic effects in pregnant rabbits exposed to 6,790, 20,370 or 61,110 mg/m3 (1,400, 4,200 or 12,600 ppm) or in pregnant rats exposed to 15,520 or 38,800 mg/m3 (3,200 or 7,900 ppm) of dichlorofluoroethane although signs of maternal toxicity were observed at and above 15,520 mg/m3 (3,200 ppm) in rats and 20,370 mg/m3 (4,200 ppm) in rabbits.

A two "generation" inhalation study in rats demonstrated a no-observed effect level of 38,800 mg/m3 (8,000 ppm) for reproductive parameters. At a higher concentration, 97,000 mg/m3 (20,000 ppm), a'"non reproducible decrease" in the number of litters, in the number of pups per litter and also some retardation of sexual maturation of male pups which may have been caused by the slight bodyweight growth retardation, was observed.

Overall dichlorofluoroethane did not present toxicologically significant genotoxic activity in vitro and in vivo.

Rats were exposed by inhalation in a lifetime study to concentrations of 7,275, 24,250 and 97,000 mg/m3 (1,500, 5,000 and 20,000 ppm). No significant evidence of toxicity was seen, however, at the highest exposure concentration reduced body weight gain was observed. Dichlorofluoroethane did not produce neoplastic changes in female rats at any test concentration. In male rats no neoplastic changes were noted at 7,275 mg/m3 (1,500 ppm) but increased incidences of testicular interstitial cell (Leydig cells) hyperplasia and adenoma were observed at 24,250 (5,000 ppm) and 97,000 mg/m3 (20,000 ppm). These changes appeared late-in life and were not correlated with increased mortality. Because of the non-genotoxicity of dichlorofluoroethane these effects on the rat Leydig cells are considered as to be of epigenetic origin and associated with senile endocrine disturbances, and therefore of no relevance to tumourigenic hazard for man.

Source:
Joint Assessment of Commodity Chemicals No. 29
HCFC-141b (1,1-Dichloro-1-Fluoroethane)
ECETOC, december 1995

HCFC-142b (1-chloro-1,1-difluoroethane)

Acute toxicity
Inhalation, LC 50, 4 h, rat : > 40 %

Irritation : Rabbit, non irritant (eyes)

Chronic toxicity:
Inhalation, after a single exposure, dog: > 5 %, cardiac sensitization following adrenergic stimulation

No carcinogenic, teratogenic effects
In vitro, Ambiguous mutagenic effect
In vivo, no mutagenic effect

Comments: Not hazardous in normal conditions
of handling and use

Source: Safety Data Sheet of Solvay