Chlorine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

5 mg/kg bw/day

Additional information

Read across from the aqueous form of chlorine (sodium hypochlorite) is scientifically justified and has been undertaken. Several reprotoxicity studies have been conducted using sodium hypochlorite.

Sodium hypochlorite data:

The reproductive effects of chlorinated water have been examined in a one-generation gavage study in rats (Carlton et al. 1986, Doc. No. 592-097). 12 males were treated with 0, 1, 2 and 5 mg av Cl/kg bw/d for 56 days and 24 females for 14 days prior to breeding and throughout the 10-day breeding period. Additionally, females received the hypochlorite solutions throughout gestation and lactation. Following breeding, the males were necropsied and evaluated for sperm parameters and reproductive tract histopathology. Adult females and some pups were necropsied at weaning on postnatal day 21. Other pups were treated post weaning until 28 or 40 days of age. These pups were evaluated for the day of vaginal patency and for thyroid hormone levels. No differences were observed between control rats and those rats exposed to up to 5 mg av Cl/kg bw/d of the test material when fertility, viability, litter size, day of eye opening or day of vaginal patency were evaluated. No alterations in sperm count, sperm direct progressive movement, percent motility or sperm morphology were observed among adult male rats. In addition, male and female reproductive organ weights were comparable to the control groups and no significant histopathological changes were observed among treated male and female rats.

In a multi-generation study highly chlorinated water, containing available chlorine at a level of 100 mg/L (corresponding to 5 mg/kg bw/d), was administered daily as drinking water to 236 BD II rats over seven consecutive generations (Duckrey 1968, Doc. No. 592-016). The first generation received the treated drinking water from an age of 100 days on, subsequent generations were treated throughout the lifetime with the exception of F3 and F4, which were treated only until weaning of their pups. Effects on the lifespan, fertility, growth, blood, organ weights and histopathology were recorded. There were no significant differences between control (2 groups of BD II rats, a total of 56 animals) and treated animals with respect to lifetime, fertility, breeding outcome, clinical signs, organ weights, haematological parameters, histopathology, neoplastic lesions. Based on this finding the parental, reproductive and developmental NOAEL is considered to be greater than 5 mg av Cl/kg bw/d.

To examine the effects on the reproductive performance groups of C3H/HeJ and C57BL/6J mice were treated with chlorinated water (10 ppm; corresponding to 1.7 mg/kg bw/d (males) and 2 mg/kg bw/d (females) acidified with hydrochloric acid (pH 2.5) over a period of 6 months (Les 1968, Doc. No. 592-017). Males and females were housed in pairs or trios and the number of pups born and weanlings were recorded. There were no adverse effects on the reproductive performance observed. Treated C3H/HeJ mice showed increased numbers of pups born and weaned in total and per dam compared to control. The percentage weaned of those born was practically identical. Treated C57BL/6J mice showed a higher reproductive performance in all evaluated parameters if the type of mating (pairs or trios) is disregarded. The number of mice weaned in the C3H/HeJ treatment group was 5.7 % greater than in the control group. In treated C57BL/6J mice the number of weaned pups was 17.5 % greater than in the respective control. There is no detrimental effect on the reproduction of mice treated with chlorinated and acidified water (10 ppm, pH 2.5); on the contrary, reproductive performance in treated animals was statistically significantly increased when compared to control. The parental, reproductive and developmental NOAEL is considered to be greater than 1.7 mg av Cl/kg bw/d (males) and 2 mg av Cl/kg bw/d (females).

Summary of toxicity to reproduction:

A number of studies in animals are available which can be used to assess the potential reprotoxic effects of chlorine administered in solution by gavage. No effects were seen in a well conducted one-generation reproductive toxicity study in rats up to a concentration of 5 mg/kg bw of available chlorine (expressed as HOCl - maximum dose tested) (Carlton, 1986) and this value is considered as NOEL for reproductive toxicity for sodium hypochlorite.

Limited epidemiological data, essentially on chlorinated drinking water is available. Two case-control studies did not identify any concern relative to pregnancy outcomes (including miscarriage). A cross-sectional study reported a possible increased risk of shorter body length and shorter cranial circumference in newborns from mothers drinking chlorinated tap water. Because of evident deficiencies in methodology and obvious bias, the results cannot be considered as reliable. A possible association between risk of spontaneous abortion and chlorinated tap water drinking has been reported in a review of a series of retrospective studies (but inconclusive because of obvious bias). In a recent prospective study, an increased risk of abortion was associated only with high consumption of cold tap water in the same area

where the association has been recorded previously but not in two others areas. This association appears to be not consistent with the causality hypothesis involving chlorinated drinking water by-products and especially THMs.

Based on available epidemiological data, there is no clear evidence of toxic effects on foetus development in human.

For Sodium hypochlorite the available studies are sufficient in their design and quality to draw the conclusion that there is no evidence to suggest that sodium

hypochlorite would present adverse effects on development or fertility. Similarly, no such evidence is forthcoming from epidemiological studies on populations consuming chlorinated drinking water.

No developmental or fertility studies in rodents are available for the inhalation route. Nevertheless, given the corrosivity of chlorine gas, it is impossible to reach blood levels of HClO or chloride which would even approach the concentrations that can be reached with sodium hypochlorite. Therefore, we can conclude that for inhalation exposure reproductive toxicity is no relevant hazard.

Short description of key information:
Read across fro the aqueous form of chlorine (sodium hypochlorite) is scientifically justified and has been undertaken.
There are no relevant studies of sodium hypochlorite per se looking at its reproductive toxicity potential in animals. However, relevant studies have been conducted using chlorine as the test substance, administered in solution by gavage or in drinking water. In a teratogenicity study, in which exposure was confined to the gestation period, no significant differences in the incidence of skeletal or soft tissue abnormalities were observed in treated groups when compared to controls. A small, but statistically significant increase in sperm head abnormalities was seen in mice, although the effect was not dose-dependant. Furthermore, no effects were seen in a well conducted one generation reproductive toxicity study in rats up to a concentration of 5 mg/kg bw of aqueous chlorine (expressed as HOCl - maximum dose tested) (Carlton, 1986). Even if the value is expressed as HOCl, it is equivalent to available chlorine since the analytical method used detects all the chlorine species in water. Therefore, the value of 5 mg/kg bw available chlorine is used in the risk characterisation as NOEL for reproductive toxicity. This value is further supported by another multi-generation study, in which also no effects were noted at doses of 5 mg/kg bw/day. Long-term toxicity studies provide also additional assurance that the substance is not a reproductive toxicant as they did not identify the testes or ovaries as target organs.
The Carlton study appears relatively more updated and reliable with a number of animals more suitable for statistical analysis. There are no studies performed at dose levels able to induce systemic toxicity. A pragmatic approach is to accept the NOEL derived from the Carlton study because it is the best study available even if no severe effects are shown in all dosed groups.

Effects on developmental toxicity

Description of key information

Read across fro the aqueous form of chlorine (sodium hypochlorite) is scientifically justified and has been undertaken.
One study with sodium hypochlorite is available. There were no treatment-related changes in viability, foetal weights and external appearance of all foetuses in all dose groups. Skeletal and soft-tissue defects were in the normal range for all dose groups. The NOAEL was set to > 5.7 mg available Cl/kg bw/day.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

5.7 mg/kg bw/day

Additional information

Read across from the aqueous form of chlorine (sodium hypochlorite) is scientifically justified and has been undertaken. Several reprotoxicity studies have been conducted using sodium hypochlorite.

Sodium hypochlorite data:

In a teratogenicity study (Abdel-Rahman et al. 1982, Doc. No., 594-064), groups of 6 female Sprague-Dawley rats were exposed to concentrations of 0, 1, 10 and 100 mg/L hypochlorite in drinking water (corresponding to 0.057, 0.57 and 5.7 mg av Cl/kg bw/d) for 2 ½ months prior to and throughout gestation. Rats were sacrificed on day 20 of gestation and foetuses were preserved for soft-tissue and skeletal examination. There were no treatment-related changes in viability, foetal weights and external appearance of all foetuses in all dose groups. Skeletal and soft-tissue defects were in the normal range for all dose groups. If skeletal and soft-tissue defects were combined a statistically significant increase was observed in the highest dose group. In the absence of a clear dose response and a relatively high incidence of defects in control animals, these findings were not considered to be of relevance. It was concluded that chlorinated drinking water at the tested concentrations is relatively harmless to the rat when fed to pregnant dams. The NOAEL for embryotoxic and teratogenic effects was considered to be greater than 5.7 mg av Cl/kg bw/d. Toxic effects on dams were not reported in this study. However, in subchronic studies which were performed at even higher dose levels than those administered in the rat teratogenicity study demonstrate an NOAEL of 57.2 mg av Cl/kg bw/d.

Justification for classification or non-classification

Although limited data are available in animals, the available studies are sufficient in their design and quality to draw the conclusion that there is no evidence to suggest that sodium hypochlorite and in conclusion also chlorine would present adverse effects on development or fertility. Similarly, no such evidence is forthcoming from epidemiological studies on populations consuming chlorinated drinking water. Thus, sodium hypochlorite/chlorine is not classified reprotoxic according to 67/548/EEC and CLP (1272/2008/EC).