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Description of key information

Skin:
A study to investigate the skin irritating potential of sodium hypochlorite (Nixon, 1975) was performed. The results indicate that sodium hypochlorite, 5.25 %, was slightly irritant in rabbits and guinea pigs under the conditions described in the study. The mean score obtained from intact skin (sum of mean erythema and edema scores at 4, 24 and 48 hours) was 1.0. All symptoms were reversible. The mean score for intact human skin was found to be 3.9 at the same concentration. These results are in line with the Specific Concentration Limits (SCL) obtained for sodium hypochlorite 67/548/EEC (DSD-DPD).
Eye:
Two eye irritation studies were conducted. New Zealand white rabbits and monkeys were treated with sodium hypochlorite solutio of approximately 5%. Signs of irritation were observed in the cornea, iris and or conjunctiva.
Respiratory tract:
The sensory respiratory irritation potential of sodium hypochlorite was assessed in the mouse with an aerosol of sodium hypochlorite (10% w/w). some sensory irritant responses were observed related to its content of chlorine. Studies in human volunteers indicated that sodium hypochlorite is irritating for the tract at concentrations above 0.5 ppm.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin

A solution of sodium hypochlorite (4.74% available chlorine) in a mixture with other ingredients used as control bleach in a patch study was applied (0.5 ml) under a semiocclusive patch on the dorsal skin of the rabbits for a 24-hour period. The skin was examined for erythema and edema directly after patch removal and 48 hours later. The evaluation of the lesions was carried out according to the FHSA Regulation (1973). A primary irritation index (PII) of 5 or higher indicates a primary irritation response in accordance with FHSA Regulations. The compound was considered to be non irritant to the rabbit skin based on the PII reported as < 5. (Osterberg et al., 1977).

Sodium hypochlorite 5.25 % solution (pH 10.7, 0.5 ml) was applied on rabbit and guinea pig abraded and non-abraded skin in a 4-hour patch test as outlined in the revised FHSA procedure that had been proposed by FDA (Edwards, 1972). The skin was examined at 4, 24 and 48 hours after patch removal. Results showed the compound to be slightly irritant to both rabbits (PII = 1.2) and guinea pigs (PII = 0.8) (Nixon et al., 1975).

0.5 ml of sodium hypochlorite 12.5 % available chlorine was applied to the intact and abraded rabbit skin for 24 h. The skin was examined for effects up to 72 hours. The scoring of the irritation response was carried out according to the Draize classification. Initial solution (12.5 %) and dilution of ½ (6.25 %) were considered as severe irritant (with PII = 5.6 for both concentrations); a dilution of ¼ (3.12 %) was considered to be moderately irritant (PII = 4.0) and a dilution of 1/8 (1.56 %) as slightly irritant (PII = 1.9) (Duprat et al., 1974). It is pointed out that Duprat used a much longer exposure time (24 hours) compared to the standard classification patch test, which recommends patching for 4 hours. This can also explain the higher scores in comparison to the Nixon study, which did use the standard 4 hours exposure time.

0.5 ml of sodium hypochlorite 12.7 % active chlorine was applied to intact and abraded rabbit skin for 24 h. The skin was examined for effects up to 72 h. Scores from intact skin and abraded skin were added and a mean was calculated. Hypochlorite at 12.7 % was considered to be moderately irritant (PII = 4.04) (Colgate-Palmolive, unpublished data-1985).

In a dermal irritancy/corrosion test on 20 compounds in aqueous solution, sodium hypochlorite solution 8-12% available chlorine applied to the dorsal skin of the rabbit, was tested at different concentrations (2, 20, 35, 50% w/v, i.e. 0.24, 2.4, 4.2 and 6 % available chlorine): The study showed slight irritation effects at the lowest concentration, moderate irritation at the other concentrations and corrosive effects at the highest concentration tested probably according to the Draize scale) (Loden et al., 1985). Based on poor reporting, the study protocol followed could not be verified, although the Draize scale appears to have been used.

The primary skin irritation score in the rabbit was found to be 5.08 using 0.5 ml of undiluted liquid. This score was an average of mean scores on intact and abraded skin. Contact time is not specified. The compound was considered as “corrosive” (Industrial Bio-Test Laboratories Inc., 1970). However, this study is considered of very limited value to assess the irritation properties of hypochlorite, as neither the test substance concentration in this study nor the exact protocol used are described.

In a primary dermal irritation study (Griffiths, Chlorine Insitute, 1978), young adult albino rabbits (6 animals) were dermally exposed to 0.5 mL of sodium hypochlorite (12.5 %) for 24 hours. The method employed was patterned after the Draize procedure as described in 16 CFR 1500.41. The only modification made was the application of the test material to two intact and two abraded skin sites in each of the 6 animals. the back of each animal was shaved free of hair: intact skin was exposed on the right half of the shaved area, and the abraded on the left half. The material (0.5 mL or 0.5 g) was introduced under a square patch of surgical gauze measuring 1 inch x 1inch. Patches were removed after 24 hours and observations recorded. observations were again made after 72 hours.

Erythema and edema were observed in the intact and abraded skin of all twelve sites. These effects persisted throughout the 72 hour observation period.

The studies from Loden and Biotest had been given a validity 4 based on too little study details reported.

Eye

An eye irritation test was carried out in rabbits by Momma et al., using the Draize method (1986). The ocular irritation score was calculated from examinations up to 21 days post exposure of 5% solution. The eyes were either left unrinsed or rinsed with water after the application of sodium hypochlorite. Scoring at 24, 48 and 72 hours revealed slight – moderate eye irritation potential in both groups. In the group where rinsing was applied, eyes had returned to normal by day 14. More persistent and more pronounced injury to the cornea and the conjunctiva was observed in the group without washing. Day 21 was the end of observation time in this study at which some effects were still noted. The study indicates that rinsing of the eyes either 4 or 30 seconds after instillation significantly reduced the degree of ocular irritation.

Osterberg also performed an eye irritation test using an unofficial ocular irritation classification method (with similarities to the FHSA and Draize methodology). A dose of 0.1ml of an otherwise unspecified mixture containing hypochlorite at a conc. of 4.74 % available chlorine, was placed into the rabbit eyes and the score for alteration was followed up to 7 days post exposure. The compound was found to be severely irritant to the rabbit eye according to the specific grading scale used. Detailed scores observed however are not reported in the study. Recovery was not complete at day 7 (Osterberg et al., 1977). It has to be noted that mixture was specified as laundry bleach by the author and contained other ingredients, which would have contributed to irritancy.

The standard Draize method was applied for the evaluation of eye irritation in the rabbit. In addition to the Draize mean average scores, a non-standard microscopic evaluation was used in the grading. Commercial sodium hypochlorite (12.5% available chlorine) and a ½dilution (6.87%) were considered severe irritants with a Draize MAS score of 60 and 49, respectively. Complete recovery was observed in week 10 for the 12.5% solution and in week 4 for the 6.25% solution. ¼Dilution (3.6%) of the solution was found to be moderately irritant with a Draize MAS of 11 and complete recovery at day 15 while a 1/8 dilution (1.85%) was found to be slightly irritant (Draize MAS 1) with complete recovery at day 4. Rinsing with 20 ml physiological saline was done at 10 sec, 1 min and 5 min after application of the test substance. Washing was also done using higher volumes of physiological saline (300 ml or 600 ml). The immediate rinse (at 10 sec with 20 ml physiological saline) was the most effective in reducing the irritant effect significantly (Duprat et al., 1974).

According to the Draize method, a quantity of 0.1 ml of sodium hypochlorite 12.7 % active chlorine was applied in rabbit eyes. At day 7, Hypochlorite 12.7% was considered to be severely irritant (MAS of 64.75). Most effects had not cleared by the end of the observation period, day 14 (Colgate-Palmolive, unpublished data-1985).

Undiluted solutions at 5.25% or 8% were found to be low to moderate eye irritants in rabbits. Specifically, a 8% concentrated solution resulted in moderate irritant effects in a Draize test, with recovery being completed within 7 days. Low irritant effects were observed when the 8% solution was tested in an LVET study (Low Volume Eye Test, applied dose = 0.01 ml), with recovery being completed in 3 days. 5.25% sodium hypochlorite was tested according to the LVET protocol only and led to low irritant effects. Exact scores are not reported in the study. The authors emphasize that the LVET provides a better correlationwith human eye irritancy experience than the Draize test. Dilutions of 1:10 of the described bleaches (0.55% and 0.8 % sodium hypochlorite) also had only a low eye irritant potential in an LVET study. It was observed that a rinse with water following the eye contact reduced the degree of irritation. (Racioppi et al., 1994).

The instillation of 0.1 ml of undiluted sodium hypochlorite (unspecified concentration) into the rabbit eye gives a MAS score for irritation of 61.3 according to the Draize methodology. The compound was considered as “severe irritant“ (Industrial Bio-Test Laboratories Inc., 1970). However, this study is considered of very limited value to assess the irritation properties of hypochlorite, as the test substance concentration in this study was not described.

Griffith et al. (1980), studied hypochlorite amongst other chemicals using the Draize scale for grading of the effects. Different dose volumes were applied (0.01, 0.03 and 0.1 ml) with the purpose of comparing the observed effects to data from human experience (literature, occupational incidents and consumer accidental exposures). 0.01 ml was considered the volume leading to effects most consistent with human eye reactions. Therefore, application of 0.01 ml (as used in the LVET protocol) was proposed to be a much more realistic test of eye hazard than the Draize test. A 5 % solution of sodium hypochlorite (pH 11.1-11.6) produced only mild transient effects in a Draize test (MAS of 11 after 1 day) when rinsed out with water in the first 30 seconds. When the LVET protocol was used (0.01 ml), similar mild and transient effects were noted. Effects had cleared completely by day 7. If 0.1 ml was applied and the eyes were not rinsed, moderate irritation effects involving the cornea and the conjunctiva occurred (MAS of 31 after 1 day). Recovery was not entirely complete at the end of the observation period (day 21). At the intermediate dosing volume of 0.03 ml applied, also moderate effects were observed (MAS of 28 at day 1) which had cleared completely by day 18 (Griffith et al., 1980).

A 15% solution of sodium hypochlorite caused severe pain and damage and there were indications that healing was not complete 2-3 weeks after exposure (Grant, 1962).

Carter and Griffith (1965) summarized effects that Buehler and Newsman (1964) observed when comparing the eye irritation potential of a sodium hypochlorite aqueous solution 5.5 % in rabbits and monkeys. The eyes were not rinsed. The Draize methodology appears to have been used. No detailed scores apart from the recovery times are reported. The irritant response was much greater in rabbits (recovery between day 7 and day 35) than in monkeys (recovery at day 2). Data were also compared to recovery dates from human exposure in factory eye accidents. The author noted that the irritation response observed in the monkey seemed to be a better indicator of eye irritation following accidental exposure in workers than the response observed in the rabbit.

Pashley et al. (1985) reported rabbit eye experiments following a Draize-related methodology. Detailed scores are not reported. Sodium hypochlorite, applied to rabbit eyes at concentration of 5.25 % NaClO produced moderate to severe conjunctival palpebral edema and hyperemia within 30 minutes of exposure with the maximum severity observed at 2 h. The eyes exposed to 5.25 % revealed corneal pitting but no ulceration. Some conjunctival edema was observed, which had not fully cleared up at day 7 (and of observation period). With a 0.52 % NaClO solution, only moderate effects were observed and the reaction was gone within 24 hours. The author pointed out that “the rabbit eye model tends to exaggerate the toxicity of agents since rabbits blink their eyes at a much lower frequency than humans” (Pashley, 1985).

In a Study by Griffiths (Chlorine insitute 1978), the eyes of each rabbit were examined with sodium fluorscein and an ultraviolet lamp (prior to investigation of the test material) and only those rabbits whose eyes were free of irritation and corneal lesions were used. A volume of o.1 mL of the test material was instilled in one eye of each rabbit by gently pulling the lower lid away from the eyeball to form a cup into which the test substance was dropped. The lids were then held together for one second and the animal released. The untreated eye served as control. The eyes were again eamined with fluorescein and the grade of ocular reaction recorded at 24, 48 and 72 h and 7 days for all ainmals using a sclar score. The eyes of 6 animals were not washed out after instillation of the test material. The eyes of three animals were washed out 30 seconds after instillation of the test material, with distilled water for approximately 10 seconds or until all test material was removed from the eye. If corneal dmage was observed at 72 h, the rabbit eyes were again examined with fluorescein daily up to 7 days or again at 14 days if corneal effects persisted.

Group I (no rinsing): Corneal and iridial effects were observed in five animals. Conjunctival effects were observed in six animals. Corneal and irridial effects cleared in two animals during the 7-day observation period and conjunctival effects persisted throughout the 7-days observation period.

Gruop II (rinsing): Irridial effects were observed in one animal and conjunctival effects were observed in three animals. Irridial effects cleared in one animal during the 48-hour reading and conjunctival effects persisted throughout the 7-day observation period.

Other Data (in-vitro)

Solutions of sodium hypochlorite were also tested “in vitro“ using different cell systems. The principal aim of the studies was to compare the results obtained “in vitro“ with the “in vivo“ Draize score methods. The results obtained “in vitro“ basically confirmed the irritation properties on the sodium hypochlorite solution obtained with the standard methodology (Chan, 1985; Borenfreund and Borrero, 1984, Borenfreund and Shopsis 1985; Shopsis and Sate, 1984). However, the use of in-vitro methods for eye irritancy assessment of hypochlorite containing products at this point in time is questionable, as current in-vitro methods are known not to realistically predict the irritant properties of oxidizing substances like hypochlorite.

Respiratory Tract

The respiratory (sensory) irritation potential of sodium hypochlorite has been assessed in the mouse and has been compared to that of chlorine. An aerosol of sodium hypochlorite was generated from a 10% v/v solution in distilled water using a glass concentric jet atomiser with cyclone. Three groups of mice (gender and age not defined) were exposed to sodium hypochlorite aerosols at atmospheric concentrations of 9.2, 5.7 or 2.6 ppm, expressed as chlorine. The particulate concentrations of each atmosphere were 24, 11 and 9 mg/m3, respectively, and the mass median aerodynamic diameter of the three aerosol atmospheres ranged from 2.3 to 4.3 μm. The RD50 value, the exposure concentration causing a 50% reduction in the respiratory rate due to respiratory irritation, for sodium hypochlorite aerosol was estimated to be 4.11 ppm, expressed as chlorine. A similar test was conducted concurrently with chlorine for which an RD50 value of 5.7 ppm was estimated. It was concluded that the similarity of the results showed that the degree of respiratory irritation seen after exposure to an aerosol of sodium hypochlorite is most likely related to its content of chlorine (Lewis, 1990).”

Human volunteer studies:

There are three relevant studies reported in which human volunteers have been exposed to chlorine. A group of 8 volunteers were exposed on a single occasion to either 0.5 or 1.0 ppm (1.5 or 3.0 mg/m3) chlorine gas for either 4 or 8 hours. Sensory irritation and a transient impairment in lung function were seen in those exposed to 1.0 ppm chlorine gas. No effects were reported in those exposed to 0.5 ppm. (Rotman et al, 1983).

A group of 8 male volunteers were exposed to either 0, 0.1, 0.3 or 0.5 ppm (0, 0.3. 0.9 or 1.5 mg/m3) chlorine gas for 6 h/d on 3 consecutive days. Each individual was

exposed to each of the four exposure scenarios in a double-blind fashion. A range of respiratory function parameters was measured and, in addition, nasal lavage fluid was analysed for a number of indicators of inflammatory cell damage. No significant effects were seen in parameters measured. 0.5 ppm was a NOAEL in the study (Schins et al, 2000).

Summary

Concerning skin irritation, some irritant responses have been recorded at around 5% hypochlorite under exaggerated conditions. Nixon et al. (1975) observed only slightly irritating effects at 5 - 5.25% available chlorine solutions in a four-hour patch test where abraded skin results were also included in the evaluation. However given the fact that in the Osterberg study, no significant irritation is observed at 4.74 % concentration where the contact time was 24 hours, the findings in the Nixon study should not raise any concern. In addition, data on human skin do not contradict this conclusion as they clearly indicate an irritating effect at 5% and above.Altough in older studies some effects were seen at lower concentrations, these would not be considered irritant according to current classification criteria.

Concerning eye irritation, some irritant responses have been recorded below 5% available chlorine on rabbits. However, the study results cannot be compared on a common basis, because different protocol variations were used and the original data on which the scores were determined are not retrievable from the study reports. All dat aobtained using the LVET method or another method (e.g. monkey) that resulted in similar effects as seen from human experience, showed reversibility of effects within short time periods. The available data from human exposure (Poison Control Centers) support Pashley’s observation (1985), according to which irritant

effects in the human eye are less severe than in rabbits. Rinsing with water shows a reduction in the irritant effects both in animals and humans.

As regards the studies by Héry et al. and Erdiger et al., these clearly report that the observed eye effects can be linked to the reaction products (found in swimming pools, e.g. chlorinated carboxyl compounds) and not to hypochlorite, therefore they are not considered in the hypochlorite assessment.

With respect to corrosivity, animal data show that a 12.7% hypochlorite solution produced severely irritant or corrosive effects to the eye. However, the same concentration applied to rabbit skin does not show corrosive effects there, as only moderate irritation was observed. For these concentrated products, data from accidents are also available (mostly from the French market). No serious or long-term consequences were associated with accidental skin and eye contact.

Sodium hypochlorite aerosols may be irritant to the respiratory tract.

Despite some difficulties in interpreting the older animal data, the overall evaluation of both animal and human data supports the current EU classification as irritant above 5% and as corrosive above 10%.

Concerning the respiratory irritation potential, a study performed in mice showed that some sensory irritant responses were observed with an aerosol of sodium hypochlorite (10% w/w) and were related to its content of chlorine. Studies in human volunteers indicated that sodium hypochlorite is sensory irritating for the tract at concentration above 0.5 ppm.


Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Skin:

With respect to the Specific Concentration Limits (SCL) sodium hypochlorite has to be labelled with C and R31-34 (“contact with acids liberates toxic gas”, “causes burns”) for products with a concentrations of 10 % (w/w) available chlorine and with Xi and R31-36/38 (“contact with acids liberates toxic gas”, “irritating to eyes and skin”) for products with concentrations of 5 % (w/w) available chlorine according to 67/548/EEC, unless test data for the mixture are available at the formulator level.

According to CLP (GHS) sodium hypochlorite has to be classified with skin corrosion cat. 1B and has to be labeled with H314 for products with a concentration of 5 % (w/w) available chlorine and with skin irritation cat. 2 and H315 for products with a concentration of 1 - 5 % (w/w) available chlorine, unless test data for the mixture are available at the formulator level.

Eye:

With respect to the Specific Concentration Limits (SCL) sodium hypochlorite has to be labelled with C and R31-34 (“contact with acids liberates toxic gas”, “causes burns”) for products with a concentrations of 10 % (w/w) available chlorine and with Xi and R31-36/38 (“contact with acids liberates toxic gas”, “irritating to eyes and skin”) for products with concentrations of 5 % (w/w) available chlorine according to 67/548/EEC, unless test data for the mixture are available at the formulator level.

According to CLP (GHS) sodium hypochlorite has to be classified with eye damage cat. 1 and has to be labeled with H318 for products with a concentration of 3 % (w/w) available chlorine and with eye irritation cat. 2 and H319 for products with a concentration of 1 - 3 % (w/w) available chlorine, unless test data for the mixture are available at the formulator level.

Respiratory tract:

With respect to the standard concentration limits (SCL) sodium hypochlorite has to be labelled with Xi and R37 ("irritating to respiratory tract) for products with concentrations of 20% (W/W) available chlorine according to 67/548/EEC.

According to CLP (GHS) sodium hypochlorite has to be classified with STOT SE 3 and has to be labelled with H 335 for products with a concentration of 20 % (w/w) available chlorine with respect to the General concentration limits (GCL).

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