Disodium fluorophosphate

Toxicity to reproduction

Administrative data

Endpoint:

multi-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Study performed does not comply with a specific test guideline, but the methods are well documented and scientifically acceptable. In addition the study has been performed in accordance with GLP. This study is considered to be comparable to a guideline study. The reliability has been restricted to reliability 2 on the basis that the study was conducted on an analogous substance (NaF). Sodium fluoride (NaF) is considered to be analogous to disodium fluorophosphate in terms of toxicological profile for the following reasons; - A combined 28-day reprotoxicity screening toxicity study (OECD 422) performed on disodium fluorophosphate confirmed the leading health effects to be consistent with the effects reported for exposure to inorganic fluorides (fluorosis). In particular severe effects were noted in the mucosal lining of the stomach and are consistent with exposure to fluoride. - Results of studies on NaF are considered to present a worst case for exposure as NaF contains approximate 47% F compared to 13% F in disodium fluorophosphate. - The phosphate content of sodium fluorophosphate is not considered to present a hazard in terms of reprotoxicity. Phosphate is an essential element; a maximum tolerable daily intake value (MTDI) for phosphates is reported to be 70 mg/kg bw/day. This value greatly exceeds the limit value placed on an inorganic fluoride (OEL = 2.5 mg/kg bw/day F) and as such is not considered to be relevant for risk assessment. This study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint as a part of a weight of evidence approach in accordance with Annex XI of Regulation EC No. 1907/2006.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2001

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The effects of sodium fluoride ingestion at 0, 25, 100, 175 and 250 ppm in drinking water were observed in rats throughout 2 generations.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium fluoride

EC Number:

231-667-8

EC Name:

Sodium fluoride

Cas Number:

7681-49-4

Molecular formula:

FNa

IUPAC Name:

sodium fluoride

Constituent 2

Reference substance name:

7861-49-4

IUPAC Name:

7861-49-4

Details on test material:

- Name of test material (as cited in study report): sodium fluoride (NaF); CAS No. 7681-49-4
- Physical state: solid
- Analytical purity: as pure as the standard reference sample purchased from the U.S. Pharmacopeia, Rockvile, MD
- Impurities (identity and concentrations): no trace element impurities were detected
- Lot/batch No.: 109F0102

Test animals

Species:

rat

Strain:

other: Caesarian-derived (CD CRL:CD-BR), viral anti-body free

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Willmington, MA, USA
- Weight at study initiation: (P) Males: 100.5 - 100.9 g; Females: 93.9 -94.8 g
- Housing: Single animals were housed in stainless-steel cages suspended in stainless-steel racks. Pregnant females and females with litters (to weaning) were housed in polycarbonate tubs with Sani-Chips (P.J. Murphy Forest Products Corp., Montville, NJ)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.7 - 22.8
- Humidity (%): 35-67
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

Weight/volume NaF solutions were prepared in water obtained by filtering house-distilled water through a Hydro Pico pure water system. The concentration of fluoride in the Pico system treated water was <0.2ppm.
The following NaF solutions were used for this study: 0 (Pico system water only), 25, 100, 175 or 250 ppm.

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Length of cohabitation: no longer than 1 week
- After 1 week of unsuccessful pairing females were re-mated to a different male within the same group
- Further mating’s after two unsuccessful attempts: yes - each female was allowed up to 3 weeks for mating.
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: presence of sperm in the vaginal lavage referred to as day 0 of pregnancy.
- Any other deviations from standard protocol: At gestation day 20, caesarean sections were performed on 8 F0 females per group. The dams and their offspring were examined, and the results are reported by Collins, T.F.X. et al. (2001) (see Developmental Toxicity endpoint). After mating, P adult males were transferred to a separate protocol for a study of the effects of sodium fluoride on male reproduction Sprando et al (1997, 1998).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Sodium fluoride concentrations for both the control and treated groups were determined at the FDA by potentiometric titration of the fluoride ion with a fluoride ion electrode by using an EA 940 pH/ISE meter with appropriate electrodes and filling solutions for fluoride analysis. Sodium fluoride concentrations were determined each time dosing solutions were prepared for any treatment group, including the control.

Duration of treatment / exposure:

F1 and F0 male and female rats were treated for 10 weeks before mating.

Frequency of treatment:

Continuous - 7 days/week

Details on study schedule:

- F1 parental animals were not mated until 10 weeks after being selected from the P litters.
- Selection of parents from F1 generation occurred when pups were 21 days of age.
- Age at mating of the mated animals in the study: Approximately 13 weeks old
- At gestation day 20, caesarean sections were performed on pregnant adult P and F1 females. The dams and their offspring were examined and the results are reported by Collins, T.F.X. et al. (2001).
- At weaning on postnatal day 21, 10 F1 males and 10 F1 females from each group were selected and given fluoride solution to postnatal day 90. Growth and feed and fluid consumption of these F1 animals were measured during postnatal days 21-90. These animals were referred to as the F1 non-mated subset.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 100 or 250 ppm
Basis:
nominal in water

No. of animals per sex per dose:

48 for the F1 generation and 48 for the F2 generation.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The 25, 100 and 175 ppm sodium fluoride doses were based on results of the National Toxicology Program (NTP 1990) chronic 2-year toxicology and carcinogenicity study in rats and mice. The 250 ppm sodium fluoride dose was based on results of a developmental study in rats conducted in the current study's laboratory in which rats tolerated this dose without adverse effects (Collins et al. 1995).

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: At study initiation and 10 weeks for P animals. At gestation day 21 and 10 weeks for F1 animals.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: At study initiation and 10 weeks for P animals. At gestation day 21 and 10 weeks for F1 animals.

Oestrous cyclicity (parental animals):

No data

Sperm parameters (parental animals):

See Sprando et al, 1997, 1998

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 13-14 pups (males/females combined)/litter; excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: Number of pups (male/female combined), number born alive, number alive on day 4 (pre-culling and post-culling), and number of alive on postnatal days 7, 14 and 21, presence of gross anomalies, and weight gain.


GROSS EXAMINATION OF DEAD PUPS: No information

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: 10 P males and 10 F1 males from each group were sacrificed soon after the last litters in each generation were produced.
- Maternal animals: 10 P and 10 F1 females from each group were sacrificed after the last litter of each generation was weaned.


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations. All gross lesions were recorded. Necropsies of remaining animals (P post-lactation females), P post-mating males, F1 extra males, and F1 non-pregnant females) were performed by the Developmental and Subchronic Toxicology Team at FDA and are not presented in this report.


HISTOPATHOLOGY / ORGAN WEIGHTS
- The animals were weighed and the following tissues were weighed: thymus, heart, kidneys, adrenal glands, brain, liver, testes, epididymides, prostate, seminal vesicle, ovaries and spleen.
-Histopathological examination of the following tissues was performed: heart, aorta, spleen, thymus, lungs, liver, kidney, pituitary and adrenal glands, thyroid gland, parathyroid gland, trachea, esophagus, stomach, duodenum, pancreas, jejunum, ileum, cecum, colon, testes, ovaries, urinary bladder, epididymides, seminal vesicle (base), prostate, uterus (bifurcation), cervix, vagina, eyes with optic nerves, mammary gland (right thoracic), sternum with marrow, brain (cerebellum, pons/medull, cerebrum), spinal cord (cervical, thoracic, lumbar), and any gross lesions. In addition, the following tissues were evaluated for animals from the control and high-dose groups (250 ppm): salivary gland, tongue, mesenteric lymph node, rectum, intraorbital lacrimal glands, psoas muscle, skin, skiull (2 sections), Harderian glands, teeth (upper incisors and upper molars), nasal turbinates, vertebral column (caudal-thoracic and caudal-lumbar), right femur with marrow and right sciatic nerve.

Postmortem examinations (offspring):

SACRIFICE
- F1 offspring (10 males and 10 females) from each group that were not selected as parental animals were sacrificed at 21 days of age.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations. All gross lesions were recorded.
HISTOPATHOLOGY / ORGAN WEIGHTS
- The F1 weanling animals were weighed and the following tissues were weighed: thymus, heart, kidneys, adrenal glands, brain, liver, testes, epididymides, prostate, seminal vesicle, ovaries and spleen.
-Histopathological examination of the following tissues was performed: heart, aorta, spleen, thymus, lungs, liver, kidney, pituitary and adrenal glands, thyroid gland, parathyroid gland, trachea, oesophagus, stomach, duodenum, pancreas, jejunum, ileum, cecum, colon, testes, ovaries, urinary bladder, epididymides, seminal vesicle (base), prostate, uterus (bifurcation), cervix, vagina, eyes with optic nerves, mammary gland (right thoracic), sternum with marrow, brain (cerebellum, pons/medulla, cerebrum), spinal cord (cervical, thoracic, lumbar), and any gross lesions. In addition, the following tissues were evaluated for animals from the control and high-dose groups (250 ppm): salivary gland, tongue, mesenteric lymph node, rectum, intraorbital lacrimal glands, psoas muscle, skin, skull (2 sections), Harderian glands, teeth (upper incisors and upper molars), nasal turbinates, vertebral column (caudal-thoracic and caudal-lumbar), right femur with marrow and right sciatic nerve

Statistics:

Statistics
Clinical signs in control and treated rats were analysed by Fisher's Exact Test. For parameters of feed consumption (two-tail), number of implants, total animals alive, males alive and females alive (one-tail), an analysis of variance (ANOVA) was performed. If the ANOVA indicated a significant effect (P equal to or less than 0.05), then a least significant difference (LSD) test was run to compare the control with each treated group. For the parameters body weight, organ weight, body weight gain, and gravid weight an analysis of covariance was performed. If the analysis of covariance showed a significant effect, a LSD test (two-tail) was run to compare the control with each treated group. Analyses of organ to body weight and organ to brain weight ratios were performed using body weight and brain weight as the covariate, respectively. For statistical analysis of mean fluid consumption, each dose group was first checked for outliers using the Grubbs outlier test (one-tail) because several animals (distributed throughout all groups) played with their water tubes, causing the fluid to drip which led to unusually and misleadingly high fluid consumption values for these animals. If an animal was deemed an outlier from the Grubbs test, it was removed from the statistical analysis of fluid consumption. Each time period for each dose group was then tested for outlying values and if a value was determined to be an outlier, a replacement value was calculated using a method described by Snedeco and Cochran (1967).

Reproductive indices:

For females of both the F0 and F1 generation, the following parameters were recorded:
- The number exposed to mating
- The number of sperm-positive (or with plug)
- The number who produced a litter
- mating index; (No. sperm-positive / no. exposed to mating)x100
- Fertility index #1; (no. producing a litter/ no. sperm-positive) X 100
- Fertility index #2; (no. producing a litter/no. exposed to mating) X 100
- Time to mating (days ±S.E.M.).

For females of both the F0 and F1 generation, the following parameters were recorded:
- The number exposed to mating
- The number producing sperm-positive females
- The number who produced a litter
- mating index; (No .produced plugs or sperm-positive females / no. exposed to mating)x100
- Fertility index #1; (no. producing a litter/ no. producing sperm-positive females) X 100
- Fertility index #2; (no. producing a litter/no. exposed to mating) X 100
- Time to mating (days ±S.E.M.).

Offspring viability indices:

The parameters used to evaluate survival of total F1 offspring (male and female) included:
- number of implants,
- number born,
- number born alive,
- number alive on day 4 (pre-culling and post culling),
- number alive on days 7, 14 and 21.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
- No dose-related clinical effects were observed in either adult males or females from the P and F1 generations. During the 10-week growth period, one F0 male died from the 25 ppm group, and one F1 male died from the control group. No other animals died during the growth period.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
- Mean body weights of females and males in the F0 and F1 generations were similar in all groups. No statistically significant effects were seen in any group. Weight gain of F0 females and males during days 0-70 showed a significant negative linear regression. Only the individual weight gain of P males in the 250 ppm group was statistically significantly less than the control. In the F1 generation, weight gain of females and males was similar; no significant dose-related effects were observed.
-No dose-related changes in body weight gain were observed in F0 females during gestation and lactation. Gravid body weight of F1 females also showed no relation to dose.
- During the 10-week growth period, there were no significant differences in feed consumption in F0 females between the control and treated groups. During the same period, there was a significant decrease in overall food consumption by F0 males in the 250 ppm group. This was due to significantly less feed consumption by the 250 ppm rats than by the control group during the first 7 weeks and week 9 (8 of the 10 weeks during the growth period). Overall mean feed consumption of F1 females showed a significant negative linear regression for days 0-70, although none of the values was significantly less than the control value. During the same period, F1 males in the treated groups consumed less feed than did the control group, but the decreases were neither dose-related nor significant.
- Feed consumption was measured during gestation and lactation of F0 females that gave birth and reared their litters, and during gestation of F1 females. During gestation, no dose-related changes were observed in feed consumption in either F0 or F1 females. During lactation, feed consumption of F0 females was similar in control and all test groups
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS):
- During the 10-week growth period, the F0 and F1 females and males in the 175 and 250 ppm groups drank significantly less than the animals in their respective control groups. F1 males in the 100 ppm group also drank significantly less than the control group. Decreased consumption was attributed to decreased palatability.
- Sodium fluoride consumption by F0 females ranged from 3.5 to 27.3 mg NaF/kg/day at 25 to 250 ppm, respectively, and consumption in F1 females was similar (3.8 to 28.0 mg NaF/kg/day, respectively, for 25 to 250 ppm). Sodium fluoride consumption by F0 males ranged from 2.8 to 23.1 mg NaF/kg/day at 25 to 250 ppm, respectively, and consumption in F1 males ranged from 3.0 to 24.1 mg NaF/kg/day, respectively, for 25 to 250 ppm.
- With respect to fluoride consumption, F0 females consumed 1.5 to 12.3 mg F/kg/day, and F1 females consumed similar amounts (1.7 to 12.7 mg F/kg/day, respectively, for 25 to 250 ppm). F0 males consumed 1.3 to 10.5 mg F/kg/day, and F1 males consumed similar amounts (1.4 to 10.9 mg F/kg/day, respectively, for 25 to 250 ppm.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
The reproductive F0 generation female mating indices were over 90% in all groups. F0 female fertility indices were decreased slightly (but not significantly) at 250 ppm. Average time to mating was less in treated groups than in the controls, but the differences were not dose-related.
Mating indices of F1 females were also over 90% indicating lack of sodium fluoride-related effects. The fertility indices of the females in the 25 and 250 ppm groups were slightly less than the control animals, but the differences were not statistically significant and are probably due to random variation. No dose-related effect was seen in the average time to mating of F1 females. The longest time to mating was seen in the 25 ppm group.
Mating indices of F0 males were not dose-related. The mating indices for P males were slightly lower than those in P females, although all values were over 90%. The lowest male fertility index occurred in the 250 ppm group, but the difference was not statistically significant. Two males in the 25 ppm group mated with two females each, but neither produced a litter; no other group contained males that mated without consistently producing a litter. The lack of dose relationship and the lack of statistical significance indicated that these decreases are probably random.
- All the mating indices of F1 males were less than those of the P males; there were no dose-related decreases. Fertility indices of F1 males were lower in the 25 and 250 ppm groups than in any other group. Because of the lack of dose response, these effects appeared to be random.
ORGAN WEIGHTS (PARENTAL ANIMALS):
In F0 females, no significant differences in organ weights were observed between control and treated groups. In P adult females weighing 320 +/- 11.1 g, organ weights were: thymus 0.38 +/- 0.04 g; heart 1.26 +/- 0.03 g; liver 15.18 +/- 0.71 g; spleen 0.63 +/- 0.03 g; both kidneys 2.78 +/-0.08 g; both adrenals 0.08 +/- 0.01 g; both ovaries 0.17 +/- 0.01 g; and brain 1.96 +/- 0.03 g. Body weight of P control adult males was 546.6 +/- 19.4 g and organ weights were: thymus 0.78 +/-0.11 g; heart 1.64 +/- 0.07 g; liver 22.75 +/- 1.24 g; spleen 0.98 +/- 0.05 g; both kidneys 4.20 +/- 0.12 g; both adrenals 0.05 +/- 0.00 g; both testes 3.49 +/- 0.06 g; brain 2.16 +/- 0.02 g; both epididymides 1.44 +/- 0.09 g; seminal vesicle 1.53 +/- 0.20 g; and prostate 1.24 +/- 0.13 g. Organ-to-body-weight rations and organ-to-brain weight ratios were calculated for all adult female and male organs, and no dose-related or significant effects were seen.
GROSS PATHOLOGY (PARENTAL ANIMALS):
In the F1 generation, no stained or mottled teeth were observed in either sex of any group. However, whitening of the teeth was observed in both females and males in the 100, 175 and 250 ppm sodium fluoride groups. Although the effect was mild, a number of affected females and males was increased in a dose-related, statistically significant manner. Animals in the 25 ppm group were not affected.

HISTOPATHOLOGY (PARENTAL ANIMALS):
Histomorphologic tissue alterations attributable to the administration of NaF consisted of an increase in the development of prominent growth lines (basophilic lines in the dentine and enamel of the teeth) in the upper incisors of all F0 rats that received 250 ppm compared to the control rats.
In the F0 generation the growth lines were graded as minimal in 8 males and 6 females and mild in 2 male and 4 female rats. Dentin deposition in the pulp cavity was also observed in 1 F0 male and 1 F0 female of the 250 ppm group.
Hyperkeratosis of the limiting ridge of the stomach (junction of the glandular stomach and the forestomach) was diagnosed in a small number of F0 animals (1 male and 3 females at 100 ppm, 1 male at 175 ppm and one female at 250 ppm. The condition appeared to be related to the toxicity of NaF and did not affect feed consumption, growth or reproduction of the animals.
Spontaneous disease lesions and incidental findings in other organs and tissues were of the usual number and type commonly observed in Sprague-Dawley rats at each age. These lesions and findings occurred at similar incidence rates in control and treated animals.

OTHER FINDINGS (PARENTAL ANIMALS):
- In 10 F1 weanlings of each sex per group that were allowed to grow to day 90 (the non-mated subset), no clinical change attributable to sodium fluoride was observed in either females or males. Overall mean feed consumption of females and males showed no significant dose-related change. Mean body weight and body weight gain of treated females and males also showed no significant dose-related changes.
- Overall mean fluid consumption by F1 females and males was decreased at 175 and 250 ppm in a dose-related manner, but only the consumption at 250 ppm was significantly reduced. The amounts of sodium fluoride and fluoride consumed by the females and males were similar to those consumed by the P and F1 animals during their 10-week growth period. The amount of sodium fluoride consumed at 250 ppm was 28.4 mg/kg/day for females and 27.1 mg/kg/day for males. Of this, fluoride consumption was 12.8 mg/kg/day for females and 12.3 mg/kg/day for males.

Effect levels (P0)

Dose descriptor:

NOAEC

Remarks:

reproduction

Effect level:

ca. 250 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Description (incidence and severity):

not reported: however F1 generation were mated successfully to produce F2 generation

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not specified

Histopathological findings:

effects observed, treatment-related

Details on results (F1)

VIABILITY (OFFSPRING)
Survival indices of F1 offspring (implantation, live-birth, day-4 survival, day-7 survival, day-14 survival and lactation indices) were calculated for combined female and male offspring, as well as female and male offspring separately. Neither significant nor dose-related effects were observed.

CLINICAL SIGNS (OFFSPRING)
Growth and development of F1 female and male pups to postnatal day 21 were similar in all groups.

BODY WEIGHT (OFFSPRING)
In F1 male and female F1 pups, no significant dose-related mean body weight changes were found. However, on day 0, a significant mean body weight increase occurred in F1 female pups dosed with 100 ppm sodium fluoride when compared to controls.

ORGAN WEIGHTS (OFFSPRING)
In F1 weanling males and females, no significant dose-related effects were observed in the organ-to-body-weight ratios or in the organ-to-brain-weight rations. In F1 weanling control females weighing 74.8 +/- 2.0 g, organ weights were: thymus 0.35 +/- 0.01 g; heart 0.41 +/- 0/01 g; liver 3.57 +/- 0.08 g; spleen 0.30 +/- 0.02 g; both kidneys 0.95 +/- 0.04 g; both adrenals 0.02 +/- 0.00 g; both ovaries 0.05 +/- 0.01 g; and brain 1.46 +/- 0.04 g. In F1 weanling control males weighing 82.0 +/- 2.5 g, organ weights were: thymus 0.36 +/- 0.02 g; heart 0.45 +/- 0.01 g; liver 3.99 +/- 0.15 g; spleen 0.35 +/- 0.02 g; both kidneys 1.04 +/- 0.04 g; both adrenals 0.03 +/- 0.00 g; both testes 0.51 +/- 0.03 g; brain 1.54 +/- 0.07 g; both epididymides 0.13 +/- 0.03; seminal vesicle 0.04 +/- 0.01; and prostate 0.09 +/- 0.01 g.


HISTOPATHOLOGY (OFFSPRING)
Histomorphological tissue alterations attributable to administration of sodium fluoride consisted of an increase in the development of prominent growth lines (basophilic lines in the dentin and enamel of the tooth) in upper incisors of 8 female and 10 male F1 weanlings that received 250 ppm compared to the controls. In weanling animals, the growth lines were graded minimal in 7 males and 5 females and mild in 6 rats, 3 of each sex. No other histological findings were noted.

Effect levels (F1)

Dose descriptor:

NOAEC

Remarks:

reproduction

Generation:

F1

Effect level:

ca. 250 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Sodium fluoride administered in the drinking water of rats up to 250 ppm (equivalent to 28.4 mg sodium fluoride/kg bw/day or 12.8 mg fluoride/kg bw/day.) had no adverse effects on the reproductive parameters assessed in this study. No cumulative toxicology was observed in the 3 generations.
This study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint as a part of a weight of evidence approach in accordance with Annex XI of Regulation EC No. 1907/2006.