Chloramide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Remarks:

other: reproductive study

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study reported here was designed to evaluate reproductive effects in rats. Males were treated for 56 days and females for 14 days prior to breeding and throughout the 10-day breeding period. Females were treated 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 postweaning until 28 or 40 days of age. These pups were evaluated for the day of vaginal potency and thyroid hormone levels.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Long-Evans

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 4-6 weeks
- Housing: 2 per cage in polycarbonate cages
- Diet : Purina Certified Roden Chow 5002, ad libitum.
- Water : deionized water, ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 69-75°F
- Humidity (%): 40-60
- Photoperiod : 12 hrs dark/12 hrs light

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Twelve males rats per dose group were gavaged with 0, 2.5, 5.0 or 10.0 mg/kg for 56 days prior to breeding and trhoughout the 10-day breeding period. Twenty -four female rats per dose group were given the same dose levels of monochloramine by gavage 14 days prior to breeding and throughout breeding, gestation, and lactation until the pups were weaned on day 21.

Details on mating procedure:

- M/F ratio per cage: 1/2
- Length of cohabitation:10-day breeding
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males were exposed to chloramine for 56 days prior to breeding and throughout the 10-day breeding period.
Females were exposed for 14 days prior to breeding and throughout breeding, gestation and lactation until the pups were weaned on day 21.

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 2.5, 5.0, or 10 mg/kg
Basis:
nominal conc.

No. of animals per sex per dose:

12 male rats per dose
24 female rats per dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses chosen were the highest practicable considering solution stability and potential gastric irritation.

Positive control:

No

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes

Oestrous cyclicity (parental animals):

No data

Sperm parameters (parental animals):

Parameters examined in male parental generations:
sperm count in epididymides, sperm motility, sperm morphology

Litter observations:

Litters were evaluated for viability, litter size, day of eye opening, body weight gain, and gross external abnormalities. The day on which all pups in a litter had both eyes open was designated as the day of eye opening. At necropsy on lactation day 21, 10 pups/sex/dose were bled for complete blood counts and hormone

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: Following the breeding period.
- Maternal animals: On lactation day 21.

GROSS NECROPSY
- Gross necropsy consisted of reproductive tract examinations.

HISTOPATHOLOGY / ORGAN WEIGHTS
Male: The reproductive tract, including testis, epididymis, prostate, and seminal vesicles, was removed weighed, and, except for the right cauda epididymis, preserved in neutral buffered formalin for histopathologic evaluation
Female: The reproductive tract was removed, weighed, and preserved for histopahtologic evaluation.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed on lactation day 21.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of reproductive tract examinations.

HISTOPATHOLOGY / ORGAN WEIGTHS
Not performed.

Statistics:

no statistics were performed.

Reproductive indices:

Not evaluated.

Offspring viability indices:

Not evaluated.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

No clinical signs of toxicity, hematology changes, or evidence of body weight suppression were observed for adult male or female rats dosed with 0, 2.5, 5.0, or 10.0 mg/kg NH2Cl by gavage for up to 72 days. Fertility, fecundity, lenght of gestation, litter size, and litter survival rates were unchanged by NH2Cl treatment. No treatment-related adverse reproductive effects were observed in adult male rats treated with up to 10.0 mg/kg NH2Cl. The sperm concentration ranged from 587.5 x 10exp6 sperm/g epididymal tissue to 644 x 10 exp6 sperm/g epididymal tissue. the percentage of abnormal sperm morphology ranged from 0.4 +/- 0.5 % to 2.6+/- 4.7 %, but did not varied in a dose-dependent manner. Sperm motility and sperm progressive movement were unaffected by dose exposure. No treatment-related histopathologic lesions were observed in the reproductive tracts of male or female rats.

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

haematology

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Litter size and litter survival rates were unchanged by NH2Cl treatment. Mean pup weight was unaltered. the average day of opening and the average day of observed vaginal patency (day 31.8 to day 32.6) were comparable among groups.

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

Reproductive effects observed:

not specified

Conclusions:

No adverse reproductive effects following subchronic administration of chloramine were observed in this study.

Executive summary:

The reproductive effects of chloramine administered by gavage in Long-Evans rats were examined. Males were treated for 56 days and females for 14 days prior to breeding and throughout the 10 -day breeding period. Females were treated 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 postweaning until 28 or 40 days of age. These pups were evaluated for the day of vaginal patency and thyroid hormone levels. No differences were observed between control rats and those rats exposed to 10 mg/kg/day chloramine when fertility, viability, litte size, day of eye opening, or day of vaginal patency were evaluated. No alterations in sperm count, sperm direct progressive movement (µm/sec), percent motility, or sperm morphology were observed among adult male rats. In addition, male and female reproductive organ weights were comparable to their respective controls groups, and no significant histopathologic changes were observed among chloramine -treated male and female rats.

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:

One study available with a klimish score = 2.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There is one data available for this endpoint.

In this teratogenic and reproductive toxicity assay, male long-evans rats were administered doses of 0, 2.5, 5 or 10 mg chloramine/kg by gavage for 56 days prior to breeding and throughout the 10 -day breeding cycle. Female rats received the same concentrations by gavage for 14 days prior to breeding and throughout breeding, gestation, and lactation, until the pups were weaned on day 21. No alterations in sperm count, sperm motility, or sperm morphology were observed. There were no dose-related effects on fertility, fetal viability, litter size, day of eye opening, or day of vaginal patency. The weights of male and female reproductive organs were not significantly different between the test and control groups, and no significant anatomical changes were seen on tissue examination. A NOAEL of 10 mg/kg of body weight per day was identified. (Carlton et., 1986).

Justification for selection of Effect on fertility via oral route:

Only one reproductive study available.

Justification for selection of Effect on fertility via inhalation route:

According to the oral available data, there is no indication of reprotoxicity. Therefore, additional inhalation testing would neither improve risk assessment nor safety of applications.

Justification for selection of Effect on fertility via dermal route:

According to the oral available data, there is no indication of reprotoxicity. Therefore, additional dermal testing would neither improve risk assessment nor safety of applications.

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

data not available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment. Nevertheless, a small number of animals were used (6 animals instead of 20/ group).

Qualifier:

no guideline followed

Principles of method if other than guideline:

Determination of the teratogenicity of monochloramine in rats, when administered prior to and throughout gestation. Six animals per group were administered 0, 1, 10 or 100 mg/l NH2Cl daily in the drinking water. After treatment for 2 1/2 months, the females were placed in the cages of untreated males in a ratio of 1 male : 3 females. Females with sperm-positive vaginal smears were placed in their original cages and allowed to drink their respective solutions throughout gestation. On day 20 of gestation females were killed and the numbers of live and dead foetuses were noted as well as resorptions. Individual foetal weights were recorded and a gross examination for external malformations was made.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: data not available
- Age at study initiation: Mature virgin female rat
- Weight at study initiation: 225-250 g
- Fasting period before study:
- Housing: three per cage
- Diet : ad libitum
- Water : ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25
- Humidity (%): 50
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 h light/ dark cycle.

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of monochloramine was then determined by titrating according to DPD method of Palin. This method also detects any small amounts of di- or trichloramines present in the solution. No trichloramine was found in the solutions, and the level of dichloramine was less than 1 % of the monochloramine concentration.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 male : 3 females
- Length of cohabitation: no data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

2 1/2 months prior to and throughout gestation.

Frequency of treatment:

Daily in the drinking water.

Duration of test:

2 1/2 months + breeding period + gestation period

Remarks:

Doses / Concentrations:
0, 1, 10 or 100 mg/l
Basis:
nominal in water

No. of animals per sex per dose:

6 animals per group

Control animals:

yes

Maternal examinations:

No data

Ovaries and uterine content:

No data

Fetal examinations:

- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]

Statistics:

Chi-square analysis was performed. (it is worth noting that the experimental unit used for all statistical analyses was the individual fetus rather than the maternal unit)

Indices:

No data

Historical control data:

No data

Details on maternal toxic effects:

Maternal toxic effects:no data

Dose descriptor:

NOAEL

Effect level:

100 mg/L drinking water

Basis for effect level:

other: no maternel effect toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Dose descriptor:

NOAEL

Effect level:

100 mg/L drinking water

Sex:

female

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Viability of fetuses:

Upon sacrifice of the dams, all fetuses were found to be viable and normal in external appearance.

Fetal weights:

Fetal weights per group were analyzed by a two-way analysis of variance. The 10 and 100 mg/l of monochloramine groups of male fetuses and the 1, 10 and 100 mg/l groups of female fetuses all showed an increased fetal weight compared with the control group, but these findings were not significantly different from the control.

Types of skeletal anomalies:

In monochloramie treatment, all groups (except 1 mg/l group for missing sternebrae) were quite similar to the control values.

The total defects after monochloramine treatment in drinking water:

The percentage of skeletal, soft-tissue and total defects (combined skeletal and soft-tissue) was calculated. With monochloramine, although the percentage of skeletal defects in the fetuses of 10 mg/l group (47.8 %) was higher than in the control (34.5 %), chi-square analysis revealed no significant difference. A slight increase in soft-tissue defects was found at all dose levels of monochloramine. The defects in all of these groups, including the control group, consisted of adrenal agenesis, dextrocardia and improper orientation of the apex of the heart. The 1 mg/l monochloramine group had one fetus with the right testicle missing. The percentage of total defects in all of the monochloramine groups was very similar to that of the control group. the experimental unit used for all statistical analyses was the individual fetus rather than the maternal unit.

Conclusions:

Under the conditions of this test, monochloramine did not produce teratogenic effects in rats.

Executive summary:

Female rats (6/group) were administered 0, 1, 10 and 100 mg/L of monochloramine daily in drinking water for 2 1/2 months prior to and throughout gestation. Female rats were sacrificed on Day 20 of gestation and fetus were examined for skeletal anomalies and other effects. Monochloramine did not produce any significant changes in rat fetuses at any dose level.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Species:

rat

Quality of whole database:

Study well documented, meets generally accepted scientific principles, acceptable for assessment. Nevertheless, a small number of animals were used (6 animals instead of 20/ group).

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

There is one data available for this endpoint.

In this teratology study, female Sprague-Dawley rats were administered monochloramine in drinking water at concentrations of 0, 1, 10, or 100 mg/L for 2.5 months prior to conception and throughout gestation. Rats were killed on day 20 of gestation, and the foetuses were examined for soft tissue and skeletal abnormalities. No increase in foetal resorptions was found in any treatment group. Monochloramine did not produce any significant changes in rat foetuses at any dose level. The reliability of these findings is reduced because of the small number of dams exposed and the lack of data on maternal toxicity (Abdel-Rahman et al., 1982).

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

Only one study available.

Justification for selection of Effect on developmental toxicity: via inhalation route:

According to the oral available data, there is no indication of reprotoxicity. Therefore, additional dermal testing would neither improve risk assessment nor safety of applications.

Justification for selection of Effect on developmental toxicity: via dermal route:

According to the oral available data, there is no indication of reprotoxicity. Therefore, additional dermal testing would neither improve risk assessment nor safety of applications.

Justification for classification or non-classification

The available data on the potential toxicity to reproduction of the substance are conclusive but not sufficient for classification according to the DSD (67/548/EEC) and CLP (1272/2008/EC) criteria.