Thionyl dichloride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

no data

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

For thionyl dichlorid no fertility studies are available.

SOCl2 is hydrolyzed rapidly and completely by water in an exothermic reaction with formation of HCl and SO2. Therefore the toxicity of the hydroysis products(HCl and SO2) is also considered. There are sufficient data on thionyl dichloride and the hydrolysis products, to conclude that thionyl dichloride and both hydrolysis products are considered to be corrosive; thionyl dichloride is labeled with R35.

The test substance undergoes immediate disintegration upon contact with water, for example the moisture of the gastrointestinal tract, the skin or the respiratory system, and sufficient relevant information on the cleavage products sulfur dioxide and hydrogen chloride is available. In the aqueous milieu of mammalian bodies the sulfur dioxide will form an equilibrium with the sulfite ion, which is further oxidised to sulfate by sulfite oxidase, which is abundantly available in mitochondria of liver, kidney and heart of eukaryotes. Endogenously occurring inorganic sulfate plays important roles in physiology, a sufficient supply with sulfate is even required for normal fetal development, excess sulfate will be excreted. Hydrogen chloride will dissociate in an aqueous milieu, as well, the resulting chloride ion also plays an important role in physiology, is abundantly available in the body anyway, and has not to be regarded as toxicologically relevant. Due to the corrosive characteristics of the test substance and its vapours, the deleterious effects on the gastrointestinal tract and the respiratory system, and the local effects on the dermal application site, would dominate over systemic or reproductive effects, anyway.

HCl:

Four groups of 10 males and 10 females (mice: B6C3F1; rats: SD and F344) individually housed were exposed to hydrogen chloride gas at concentrations of 0, 10, 20 and 50 ppm for 90 days (6 hours/day, 5 days/week). For male and female mice at 50 ppm, a decrease in body weight gain, food consumption and liver weight (male) was noted. For male SD rats at 50 ppm, a decrease in food consumption was observed. For F344 rats, a decrease in body weight gain was observed in males at 50 ppm and a decrease in food consumption was observed in both sexes at 20 and 50 ppm.

No biologically significant difference was observed in urinalysis, haematology and serum chemistry. Inflammatory histo-pathological changes in lips or nasal cavity were observed in B6C3F1 mice and F344 rats above 10 ppm or in SD rats above 20 ppm. In addition, the histopathological examination of reproductive organs (testis, epididymis, prostate, seminal vesicle; ovary, uterus, oviduct, mammary glands) could not find any exposure related effects. The NOAEL for repeated dose inhalation toxicity, except for the local effects of irritation, is considered to be 20 ppm for rats and mice (OECD SIDS for HCl).

OECD SIDS assessment published in 2002 “ Because protons and chloride ions are normal constituents in the body fluid of animal species, low concentrations of hydrogen chloride gas/mist or solution do not seem to cause adverse effects to animals. In fact, the cells of gastric glands secrete hydrochloric acid into the cavity of the stomach and orally administered sulfuric acid, which results in pH change as well, did not cause developmental toxicity to laboratory animals. These facts indicate that hydrogen chloride/ hydrochloric acid is not expected to have developmental toxicity. In addition, no effects on the gonads were observed in a good quality 90-day inhalation study up to 50 ppm” (OECD SIDS 2002).

the German “Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area” concluded: “Hydrogen chloride at the pH value of biological systems dissociates completely into protons and chloride ions. Provided the MAK value is observed, the amount of chloride ions taken up from 30 mg (assuming 10 m3 respiratory volume, 100 % retention) is equivalent to 1/200 of the daily intake of chloride ions from 6 g (Jungermann and Möhler 1984). In analogy to the estimation for formic acid (MAK value 5 ml/m3) it can be concluded that 2 ml hydrogen chlroide/m3 does not lead to a marked change of the blood pH.” (MAK 2004). Since the MAK value for HCl derived at that time (3 mg/m3 ) is significantly larger than the thionyl dichloride DNEL for worker of 1 mg/ m3(see chapter DNEL calculation for further details) the conclusion drawn by the German MAK commission can be considered conservative and directly applied to the actual risk assessment of thioncl dichloride.

In conclusion, neither the hydrogen, nor the chloride ion is present at biologically relevant doses after exposure to thionyl dichloride at the worker long term DNEL.

SO2:

Adult male and female CD-1 mice were exposed to different SO2 concentrations (0, 5, 12, or 30 ppm) for 24 hours, from 9 days before the formation of breeding pairs to pregnany day day 12 -14. This exposure was near continuous, covering about 80% of the total time indicated.The offspring of exposed dams were cross-forstered shortly after birth to dams not previously exposed.

This SO2 exposure at any concentration did not affect mating (100%) in all groups), proportion of successful pregancies (100% in all groups), litter size, sex ratio, or neonatal mortality (1, 0, 2, and 1 nonviable litters in the 0, 5, 12, and 30 ppm groups, respectively, including failures of the cross-forsting procedure). Reproductive performance as well as postnatal somatic and neurobehavioural development of the offspring (the latter assessed by an observational test battery including eight reflexes and responses) were not affected by SO2 (Petruzzi S et al., Behavioural disturbances in adult CD-1 mice and absence of effects on their offspring upon SO2 exposure, Arch Toxicol (1996) 70: 757 -766).

Sulfur dioxide is readily soluble in water and is converted on the moist mucosa to sulfurous acid (H2SO3). In a further oxidation step sulfurous acid is metabolized to sulfuric acid. Excess sulfate is excreted via urine. According to the German “Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area” (1998) theoretical calculations on the sulfate concentrations demonstrate that no toxicologically relevant increase in the sulfate concentration in the humans can be assumed inhaling SO2 in the occupational setting and, consequently, a developmental or reproductive effect is not anticipated. In their calculation the panel considered quantitative conversion of sulfur dioxyde to sulfate. Exposure level was calculated based on air concentrations of 1.3 mg/m3 over an entire 8 hours shift (=10 m3 air), a volume of distribution of 4.5 l and no increase in urinary sulfate excretion was also considered as worst case assumptions. Based on these assumptions the sulfate concentration in the blood might increase by approx. 3 mg/l. Based on the normal sulfate concentration in blood (8.4 – 19.5 mg/l) and a daily excretion rate of ca. 750 mg sulfate/l urine the authors conclude that no significant increase in sulfate is assumed in humans. These calculations were confirmed by experimental studies in mice and rabbits where no reproductive toxicity was observed even at doses where slight maternal toxicity was observed.

In conclusion, neither the hydrogen, nor the sulfate ion is present at biologically relevant doses after exposure to thionyl dichloride at the worker long term DNEL.

Overall conclusion, from the available data for HCl and SO2 toxicity to reproduction is not expected.The available data on HCl and SO2 clearly indicate that the hydrolysis products do not have systemic toxicity at relevant doses without severe local effects. Since local irritation is not relevant for the endpoints reproductive toxicity, it should be concluded that thionyl dichloride is considered to be of low toxicological potential for endpoints relevant to reproductive toxicity. This conclusion is consistent with evaluations on the hydrolysis products HCl and SO2 which conclude both hydrolysis products do not have any effects on development and/or reproduction at human relevant doses (e.g. MAK 1998, MAK 2004, TRGS900 2006, TRGS900 2011, OECD SIDS 2002, ECB 2000, CIIT 1984, Upotn and L’Estrange, 1977, Clausing and Gottschalk 1989, BIBRA 1990).

Short description of key information:
Overall conclusion, from the available data for HCl and SO2 toxicity to reproduction is not expected.The available data on HCl and SO2 clearly indicate that the hydrolysis products do not have systemic toxicity at relevant doses without severe local effects. Since local irritation is not relevant for the endpoints reproductive toxicity, it should be concluded that thionyl dichloride is considered to be of low toxicological potential for endpoints relevant to reproductive toxicity. This conclusion is consistent with evaluations on the hydrolysis products HCl and SO2 which conclude both hydrolysis products do not have any effects on development and/or reproduction at human relevant doses (e.g. MAK 1998, MAK 2004, TRGS900 2006, TRGS900 2011, OECD SIDS 2002, ECB 2000, CIIT 1984, Upotn and L’Estrange, 1977, Clausing and Gottschalk 1989, BIBRA 1990).

Effects on developmental toxicity

Description of key information

Overall conclusion, from the available data for HCl and SO2 toxicity to reproduction is not expected.The available data on HCl and SO2 clearly indicate that the hydrolysis products do not have systemic toxicity at relevant doses without severe local effects. Since local irritation is not relevant for the endpoints reproductive toxicity, it should be concluded that thionyl dichloride is considered to be of low toxicological potential for endpoints relevant to reproductive toxicity. This conclusion is consistent with evaluations on the hydrolysis products HCl and SO2 which conclude both hydrolysis products do not have any effects on development and/or reproduction at human relevant doses (e.g. MAK 1998, MAK 2004, TRGS900 2006, TRGS900 2011, OECD SIDS 2002, ECB 2000, CIIT 1984, Upotn and L’Estrange, 1977, Clausing and Gottschalk 1989, BIBRA 1990).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

For thionyl dichlorid no developmental toxicity studies are available.

SOCl2 is hydrolyzed rapidly and completely by water in an exothermic reaction with formation of HCl and SO2. Therefore the toxicity of the hydroysis products(HCl and SO2) is also considered. There are sufficient data on thionyl dichloride and the hydrolysis products, to conclude that thionyl dichloride and both hydrolysis products are considered to be corrosive; thionyl dichloride is labeled with R35.

Thionyl dichloride undergoes immediate disintegration upon contact with water, for example the moisture of the gastrointestinal tract, the skin or the respiratory system, and sufficient relevant information on the cleavage products sulfur dioxide and hydrogen chloride is available. In the aqueous milieu of mammalian bodies the sulfur dioxide will form an equilibrium with the sulfite ion, which is further oxidised to sulfate by sulfite oxidase, which is abundantly available in mitochondria of liver, kidney and heart of eukaryotes. Endogenously occurring inorganic sulfate plays important roles in physiology, a sufficient supply with sulfate is even required for normal fetal development, excess sulfate will be excreted. Hydrogen chloride will dissociate in an aqueous milieu, as well, the resulting chloride ion also plays an important role in physiology, is abundantly available in the body anyway, and has not to be regarded as toxicologically relevant. Due to the corrosive characteristics of the test substance and its vapours, the deleterious effects on the gastrointestinal tract and the respiratory system, and the local effects on the dermal application site, would dominate over systemic or reproductive effects, anyway.

HCl:

Four groups of 10 males and 10 females (mice: B6C3F1; rats: SD and F344) individually housed were exposed to hydrogen chloride gas at concentrations of 0, 10, 20 and 50 ppm for 90 days (6 hours/day, 5 days/week). For male and female mice at 50 ppm, a decrease in body weight gain, food consumption and liver weight (male) was noted. For male SD rats at 50 ppm, a decrease in food consumption was observed. For F344 rats, a decrease in body weight gain was observed in males at 50 ppm and a decrease in food consumption was observed in both sexes at 20 and 50 ppm.

No biologically significant difference was observed in urinalysis, haematology and serum chemistry. Inflammatory histo-pathological changes in lips or nasal cavity were observed in B6C3F1 mice and F344 rats above 10 ppm or in SD rats above 20 ppm. In addition, the histopathological examination of reproductive organs (testis, epididymis, prostate, seminal vesicle; ovary, uterus, oviduct, mammary glands) could not find any exposure related effects. The NOAEL for repeated dose inhalation toxicity, except for the local effects of irritation, is considered to be 20 ppm for rats and mice (OECD SIDS for HCl).

OECD SIDS assessment published in 2002 “ Because protons and chloride ions are normal constituents in the body fluid of animal species, low concentrations of hydrogen chloride gas/mist or solution do not seem to cause adverse effects to animals. In fact, the cells of gastric glands secrete hydrochloric acid into the cavity of the stomach and orally administered sulfuric acid, which results in pH change as well, did not cause developmental toxicity to laboratory animals. These facts indicate that hydrogen chloride/ hydrochloric acid is not expected to have developmental toxicity. In addition, no effects on the gonads were observed in a good quality 90-day inhalation study up to 50 ppm” (OECD SIDS 2002).

the German “Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area” concluded: “Hydrogen chloride at the pH value of biological systems dissociates completely into protons and chloride ions. Provided the MAK value is observed, the amount of chloride ions taken up from 30 mg (assuming 10 m3 respiratory volume, 100 % retention) is equivalent to 1/200 of the daily intake of chloride ions from 6 g (Jungermann and Möhler 1984). In analogy to the estimation for formic acid (MAK value 5 ml/m3) it can be concluded that 2 ml hydrogen chlroide/m3 does not lead to a marked change of the blood pH.” (MAK 2004). Since the MAK value for HCl derived at that time (3 mg/m3 ) is significantly larger than the thionyl dichloride DNEL for worker of 1 mg/ m3(see chapter DNEL calculation for further details) the conclusion drawn by the German MAK commission can be considered conservative and directly applied to the actual risk assessment of thioncl dichloride.

In conclusion, neither the hydrogen, nor the chloride ion is present at biologically relevant doses after exposure to thionyl dichloride at the worker long term DNEL.

SO2:

Adult male and female CD-1 mice were exposed to different SO2 concentrations (0, 5, 12, or 30 ppm) for 24 hours, from 9 days before the formation of breeding pairs to pregnany day day 12 -14. This exposure was near continuous, covering about 80% of the total time indicated.The offspring of exposed dams were cross-forstered shortly after birth to dams not previously exposed.

This SO2 exposure at any concentration did not affect mating (100%) in all groups), proportion of successful pregancies (100% in all groups), litter size, sex ratio, or neonatal mortality (1, 0, 2, and 1 nonviable litters in the 0, 5, 12, and 30 ppm groups, respectively, including failures of the cross-forsting procedure). Reproductive performance as well as postnatal somatic and neurobehavioural development of the offspring (the latter assessed by an observational test battery including eight reflexes and responses) were not affected by SO2 (Petruzzi S et al., Behavioural disturbances in adult CD-1 mice and absence of effects on their offspring upon SO2 exposure, Arch Toxicol (1996) 70: 757 -766).

Sulfur dioxide is readily soluble in water and is converted on the moist mucosa to sulfurous acid (H2SO3). In a further oxidation step sulfurous acid is metabolized to sulfuric acid. Excess sulfate is excreted via urine. According to the German “Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area” (1998) theoretical calculations on the sulfate concentrations demonstrate that no toxicologically relevant increase in the sulfate concentration in the humans can be assumed inhaling SO2 in the occupational setting and, consequently, a developmental or reproductive effect is not anticipated. In their calculation the panel considered quantitative conversion of sulfur dioxyde to sulfate. Exposure level was calculated based on air concentrations of 1.3 mg/m3 over an entire 8 hours shift (=10 m3 air), a volume of distribution of 4.5 l and no increase in urinary sulfate excretion was also considered as worst case assumptions. Based on these assumptions the sulfate concentration in the blood might increase by approx. 3 mg/l. Based on the normal sulfate concentration in blood (8.4 – 19.5 mg/l) and a daily excretion rate of ca. 750 mg sulfate/l urine the authors conclude that no significant increase in sulfate is assumed in humans. These calculations were confirmed by experimental studies in mice and rabbits where no reproductive toxicity was observed even at doses where slight maternal toxicity was observed.

In conclusion, neither the hydrogen, nor the sulfate ion is present at biologically relevant doses after exposure to thionyl dichloride at the worker long term DNEL.

Overall conclusion, from the available data for HCl and SO2 toxicity to reproduction is not expected.The available data on HCl and SO2 clearly indicate that the hydrolysis products do not have systemic toxicity at relevant doses without severe local effects. Since local irritation is not relevant for the endpoints reproductive toxicity, it should be concluded that thionyl dichloride is considered to be of low toxicological potential for endpoints relevant to reproductive toxicity. This conclusion is consistent with evaluations on the hydrolysis products HCl and SO2 which conclude both hydrolysis products do not have any effects on development and/or reproduction at human relevant doses (e.g. MAK 1998, MAK 2004, TRGS900 2006, TRGS900 2011, OECD SIDS 2002, ECB 2000, CIIT 1984, Upotn and L’Estrange, 1977, Clausing and Gottschalk 1989, BIBRA 1990).

Toxicity to reproduction: other studies

Additional information

no data

Justification for classification or non-classification

Based on the available data for HCl and SO2 toxicity to reproduction is not expected.The available data on HCl and SO2 clearly indicate that the hydrolysis products do not have systemic toxicity at relevant doses without severe local effects. Since local irritation is not relevant for the endpoints reproductive toxicity, it should be concluded that thionyl dichloride is considered to be of low toxicological potential for endpoints relevant to reproductive toxicity. This conclusion is consistent with evaluations on the hydrolysis products HCl and SO2 which conclude both hydrolysis products do not have any effects on development and/or reproduction at human relevant doses (e.g. MAK 1998, MAK 2004, TRGS900 2006, TRGS900 2011, OECD SIDS 2002, ECB 2000, CIIT 1984, Upotn and L’Estrange, 1977, Clausing and Gottschalk 1989, BIBRA 1990).