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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-4 (Reproduction and Fertility Effects)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Directive 87/302/EEC Part B
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japan 59 Nohsan No. 4200
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Test material form:
other: Amber liquid
Details on test material:
- Name of test material (as cited in study report):Kathon(TM) 886F biocide
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Rohm and Haas, Batch No. 0157A001

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Stability under test conditions: Stable at room temperature
- Solubility and stability of the test substance in the solvent/vehicle: Soluble and stable
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: No

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Dilution in water
- Final dilution of a dissolved solid, stock liquid or gel: 30, 100, 300 ppm a.i.

OTHER SPECIFICS: Purity of test material was 14.8%

Test animals

Species:
rat
Strain:
other: Crl:CD BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Hollister, California, USA
- Age at study initiation: (P) 6-7 wks; (F1) 3 wks
- Weight at study initiation: (P) Males: 240-290 g; Females: 170-195 g
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prepared fresh once per week by diluting the test material with water
Details on mating procedure:
- M/F ratio per cage: 1 to 1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: vaginal plug or sperm in vaginal smear, referred to as day 0 of pregnancy
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical results of the dosing solutions confirmed that the water preparation procedure provided homogeneous mixtures of the test substance in water, the Kathon™ 886F biocide concentrations ranged from 90-105 % of nominal target concentrations at all levels, and Kathon™ 885F biocide is stable in water for at least 14 days at room temperature.
Duration of treatment / exposure:
10 weeks
Frequency of treatment:
Continuous, drinking water with test substance was renewed weekly
Details on study schedule:
- Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study: 6-7 weeks
Doses / concentrationsopen allclose all
Dose / conc.:
30 ppm (nominal)
Remarks:
Based on a.i.
Dose / conc.:
100 ppm (nominal)
Remarks:
Based on a.i.
Dose / conc.:
300 ppm (nominal)
Remarks:
Based on a.i.
No. of animals per sex per dose:
26/sex/group
Control animals:
yes, concurrent no treatment
other: water with inorganic salt (stabilizer) content of highest dose
Details on study design:
- Rationale for animal assignment (if not random): Animals were assigned to dose groups using a computerized randomisation procedure based on body weight.
Positive control:
n/a

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for male and female animals until cohabitation. Females weighed on Days 0,7, 14 and 21 of gestation, and Days 0,4,7, 14 and 21 of lactation. Determined every four weeks after cohabitation for unmated females and males for health monitoring purposes.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Weekly for male and female animals until cohabitation. During gestation, feed consumption was measured from Days 0-7, 7-14 and 14-2 1. Feed consumption was only measured during lactation from Days 0-7 and 7-14 due to the pups interfering with consumption from Days 14-21.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Weekly for male and female animals until cohabitation. During gestation, water consumption was measured from Days 0-7, 7-14 and 14-2 1. Water consumption was only measured during lactation from Days 0-7 and 7-14 due to the pups interfering with consumption from Days 14-21.
Oestrous cyclicity (parental animals):
During the three weeks immediately prior to mating, estrus cycling was evaluated in all P1 and P2 females by examination of cytology in daily vaginal lavage samples. This examination continued during cohabitation until positive evidence of mating was noted.
Sperm parameters (parental animals):
Parameters examined in P and F1 male parental generations:
sperm count in testes, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility, sperm morphology.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter were possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring:
number and sex of pups, stillbirths, live births, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Maternal animals: All surviving animals after the last litter of each generation was weaned.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
- Organ weights: adrenals, brain, kidneys, liver, spleen, thymus, ovary, uterus, testes, single epididymis (total and cauda), seminal vesicles (with coagulating glands and their fluids) and prostate.
- Tissues saved and fixed: adrenals, brain, kidneys, liver, pituitary, spleen, thymus, gross lesions, ovary, oviducts in females, uterus with cervix, testes, epididymis, seminal vesicles (with coagulating glands), prostate and stomach.
Postmortem examinations (offspring):
SACRIFICE
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the thoracic and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
- Organ weights: brain, spleen, thymus on one pup/sex/litter at weaning post natal day 21.
- Microscopic examination of the stomach
Statistics:
The litter (i.e., proportion of pups/litter, or litter mean) was used, where appropriate, as the experimental unit for the purpose of statistical evaluation. ANOVA and Fisher's Exact test were used to analyze the parameters studied. The level of statistical significance selected was p<0.05.
Reproductive indices:
Gestation index, mating index, fertility index.
Offspring viability indices:
Viability index, lactation index.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Males exposed to 300 ppm showed a treatment-related decrease (5 %) in mean body weight during weeks 1 through 6 of treatment.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Males exposed to 300 ppm showed a treatment-related decrease (5 %) in mean body weight during weeks 1 through 6 of treatment.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Treatment-related and concentration-dependent decreases in water consumption were noted in all-Kathon™ exposed groups through most of the premating, gestation and lactation periods.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Treatment-related and concentration-dependent decreases in water consumption were noted in all-Kathon™ exposed groups in both the P1 and P2 animals through most of the premating, gestation and lactation periods.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Treatment-related microscopic findings were limited to the stomach of male and female parental animals at 100 and/or 300 ppm. These changes included an increased incidence of focal superficial erosions of the glandular mucosa, edema and inflammation of the submucosa of the glandular and nonglandular areas, and hyperplasia and hyperkeratosis of the nonglandular stomach.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
30 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: overall effects

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Treatment-related and concentration-dependent decreases in water consumption were noted in all-Kathon™ exposed groups through most of the premating, gestation and lactation periods.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related microscopic findings were limited to the stomach of male and female parental animals at 100 and/or 300 ppm. These changes included an increased incidence of focal superficial erosions of the glandular mucosa, edema and inflammation of the submucosa of the glandular and nonglandular areas, and hyperplasia and hyperkeratosis of the nonglandular stomach.
Histopathological findings: neoplastic:
not specified
Other effects:
not examined

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P1)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
30 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
body weight and weight gain
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
300 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: reproduction and development
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
not examined

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Effect levels (F2)

Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
300 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
viability
clinical signs
histopathology: non-neoplastic

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Rats exposed to Kathon™ 886F biocide in the drinking water for two generations had a NOAEL for parental animal toxicity of 30 ppm (2.8-4.4 mg/kg/day in the P1 animals and 4.3-5.5 mg/kg/day in the P2 animals). The reproductive and developmental NOEL was 300 ppm (22.7-28.0 mg/kg/day in the P1 animals and 35.7-39.1 mg/kg/day in the P2 animals).
Executive summary:

Kathon™biocide: two-generation reproductive toxicity study in rats. No treatment-related deaths or clinical signs of systemic toxicity in either sex up to and including 300 ppm. No treatment-related effects on body weights up to and including 100 ppm in males and females and 300 ppm in females. In 300 ppm males, a treatment-related decrease (5 %) in mean body weight was seen during weeks 1 through 6 of treatment. No treatment-related effects on premating feed consumption in either sex at any dose level. Treatment-related and concentration-dependent decreases in water consumption were noted in all-Kathon™ exposed groups in both the P1 and P2 animals through most of the premating, gestation and lactation periods. No treatment-related effects on any endpoint of mating or fertility in either generation at any dose level. No treatment related effects on sperm motility, testicular sperm count or caudal epididymal reserves of P1 and P2 males at any dose level. Treatment-related microscopic findings were limited to the stomach of male and female parental animals at 100 and/or 300 ppm. These changes included an increased incidence of focal superficial erosions of the glandular mucosa, edema and inflammation of the submucosa of the glandular and nonglandular areas, and hyperplasia and hyperkeratosis of the nonglandular stomach. Rats exposed to Kathon™ 886F biocide in the drinking water for two generations had a NOAEL for parental animal toxicity of 30 ppm (2.8-4.4 mg/kg/day in the P1 animals and 4.3-5.5 mg/kg/day in the P2 animals). The reproductive and developmental NOEL was 300 ppm (22.7-28.0 mg/kg/day in the P1 animals and 35.7-39.1 mg/kg/day in the P2 animals).