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Key value for chemical safety assessment

Effects on fertility

Description of key information
No relevant information available.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
High: based on reliable sources, however read across, therefore an additional uncertainty factor of 2 was applied to the NOAEL of the subchronic toxicity study (20 mg/kg bw/day)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No reproductive toxicity testing was available for Chloramine B trihydrate, however weight of evidence for absence of reproductive toxicity potential was obtained from following sources:

1. Chloramine B trihydrate was tested in a key 90-day oral gavage toxicity study at dose levels 20, 60, 180 mg/kg bw/day (Valásková, 2007b - see Section 7.5 Repeated dose toxicity). There were no morphological or histopathological findings in the reproductive organs. The LOAEL for systemic toxicity in males and females was established as 60 mg/kg bw/day. The NOAEL (No Observed Adverse Effect Level) for males and females was set at 20 mg/kg bw/day.

2. Para-Toluenesulfonamide (a metabolite from Chloramine T) was tested in a repeated dose toxicity and reproductive/developmental toxicity screening test according to OECD TG 422 (EMEA 1999; Haneke - NIEHS, 2002). Rats were treated by gavage with 0, 120, 300 or 750 mg/kg bw, males for 42 days before mating and females for 14 days before mating up to day 3 of lactation. Parental toxicity was observed at 300 and 750 mg/kg:day based on clinical observations, weight gain and food consumption, and clinical chemistry. Litter toxicity was observed at 750 mg/kg/day based on reduced litter size and body weight, however considered to be secondary to parental toxicity. NOAEL for parental toxicity was 120 mg/kg/day; NOAEL for F1 generation was 300 mg/kg. The estimated dose of low concern for reproduction was calculated as 0.6 mg/kg/day.

3. A two-generation lifetime feeding study in Sprague-Dawley rats with the related substance ortho-Toluenesulfonamide was conducted at dietary concentrations of 0, 2.5, 25 or 250 mg/kg feed, or 250 mg/kg feed combined with 1% NH4Cl in drinking water (EMEA, 1999). The dietary levels were equivalent to approximately 0.125, 1.25, 12.5 and 12.5 mg/kg bw/day. Systemic toxicity was observed only in F0 and F1 at the top dose level (reduced weight gain and reactive hyperplasia and haemosiderosis of the spleen, and centrilobular foci of basophilic cells and peliosis in liver). However, no histological alterations were consistently present in both sexes of both generations, and no impaired fertility or indications of teratogenic effects were seen up to the highest dose level. The NOEL for systemic toxicity was 25 mg/kg feed, equivalent to 1.25 mg/kg bw/day; NOEL for reproductive toxicity in F1 & F2 was at least 12.5 mg/kg bw/day.

A read-across justification was worked out and separately attached in Section 13. Based on the data from the repeated dose toxicity studies, as well as the comparable molecular structure and similar physicochemical properties, it was concluded that both data from Chloramine B trihydrate as those of Chloramine T and metabolites such as BSA and p- and o-TSA can be used for read-across.

In conclusion, the various study types for assessment of reproductive toxicity were available with either Chloramine B trihydrate and o- and p-Toluenesulfonamide. From these 3 studies, it was demonstrated that there was no direct reproductive toxicity, and if there were any litter findings, they were secondary to parental toxicity at high systemic dose levels. Therefore further reproductive toxicity testing with Chloramine B was waived, taking into account an additional uncertainty factor of 2 based on the lower NOEL in the 2 -generation study (12.5 mg/kg bw/day) compared to the NOAEL in the subchronic toxicity study with Chloramine B trihydrate (20 mg/kg bw/day).


Short description of key information:
Repeated/reproductive toxicity screening and 2-generation study types were available for the related substances Chloramine B trihydrate and o- and p-Toluenesulfonamide. From these studies, it was demonstrated that there was no direct potential for reproductive toxicity, therefore further reproductive toxicity testing with Chloramine B was waived, taking into account an additional uncertainty factor of 2 on the lowest NOAEL of 20 mg/kg bw/day.

Justification for selection of Effect on fertility via oral route:
Further reproductive toxicity is waived.

Effects on developmental toxicity

Description of key information
Prenatal developmental toxicity of Chloramine B (trihydrate)  was tested in rabbits at dose levels of 10, 30 and 90 mg/kg bw/day by oral gavage. The no-observed-effect level (NOEL) both for the maternal toxicity and embryotoxicity was 10 mg/kg bw /day. Higher dose levels resulted in increased incidences of total skeletal retardations, in particular sternebra(e) not ossified, and developmental retardations in the form of reduced placental and fetal body weights. No test item related malformations were noted during external, internal or skeletal examination (according to DAWSON) of the fetuses. A supporting  embryotoxicity/teratogenicity study in rats was conducted by oral gavage on gestational days 6 to 15 with 0, 50, 250 or 500 mg/kg bw of a mixture of para-toluenesulfonamide (68%) and ortho-toluenesulfonamide (32%). At 250 and 500 mg/kg bw maternal weight gain was significantly reduced during the treatment period. At the same dose levels, postimplantation loss showed a dose-related increase and foetal weight was reduced. No teratogenic effect was observed. The NOELs for maternal toxicity and embryotoxicity/fetotoxicity were 50 mg/kg bw.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
High
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

Chloramine B trihydrate was administered to female rabbits at dose levels of 10, 30 and 90 mg/kg bw/day orally, by gavage from the 6th to 28th day of pregnancy (Hansen, 2011; key study). In addition, a restricted feeding control was employed consisting of untreated dams which were offered the food amount consumed by the high dose dams. Under the present test conditions, the no-observed-effect level (NOEL) was 10 mg/kg bw/day for the dams. Transient slight or moderate reductions were noted for the body weight and food intake of the dams treated with 30 mg /kg bw/day. Distinct reductions of body weight and food consumption, especially during the first days of treatment, were noted at 90 mg/kg bw/day. Similar reductions of body weight and food intake were noted in the untreated dams with restricted feeding. The no-observed-effect level (NOEL) for the fetal organism also was 10 mg/kg bw /day. A dose level of 30 mg/ kg bw /day resulted in increased incidences of total skeletal retardations, in particular sternebra(e) not ossified. The severely materno-toxic dose level of 90 mg/kg bw /day resulted in developmental retardations in the form of reduced placental and fetal body weights compared to the control. Skeletal examination (according to DAWSON) revealed increased fetal incidences for variations of the sternum (fusions) and total skeletal variations as well as retardations of the sternum and lumbar vertebral bodies (incomplete or missing ossification) and total skeletal retardations. No test item related malformations were noted during external, internal or skeletal examination (according to DAWSON) of the fetuses or soft tissue examination of the fetal heads (according to WILSON) at any tested dose level, not even at materno-toxic dose levels. No embryotoxic changes were noted for the restricted feeding group. In conclusion, the test item possessed no teratogenic properties. Chloramine B trihydrate revealed slight embryotoxicity at materno-toxic dose levels (30 or 90 mg/ kg bw/day).

A supporting embryotoxicity/teratogenicity study in rats was conducted by oral gavage on gestational days 6 to 15 with 0, 50, 250 or 500 mg/kg bw of a mixture of para-toluenesulfonamide (68%) and ortho-toluenesulfonamide (32%). At 250 and 500 mg/kg bw maternal weight gain was significantly reduced during the treatment period. At the same dose levels, postimplantation loss showed a dose-related increase and foetal weight was reduced.No teratogenic effect was observed. The NOELs for maternal toxicity and embryotoxicity/fetotoxicity were 50 mg/kg bw.

A read-across justification was worked out and separately attached in Section 13. Based on the data from the repeated dose toxicity studies, as well as the comparable molecular structure and similar physicochemical properties, it was concluded that both data from Chloramine B trihydrate as those of Chloramine T and metabolites such as BSA and p- and o-TSA can be used for read-across.

A read-across justification was worked out and separately attached in Section 13. Based on the data from the repeated dose toxicity studies, as well as the comparable molecular structure and similar physicochemical properties, it was concluded that both data from Chloramine B trihydrate as those of Chloramine T and metabolites such as BSA and p- and o-TSA can be used for read-across.


Justification for selection of Effect on developmental toxicity: via oral route:
Key study

Justification for classification or non-classification

Chloramine B trihydrate does not need to be classified for reproductive and developmental toxicity according to the Directive 67/548/EEC, Annex VI and CLP regulation (No. 1272/2008 of 16 December 2008).