Disodium fluorophosphate

Endpoint summary

Description of key information

A repeated dose toxicity study with reproduction/developmental toxicity screening test in the rat (OECD Method 422) via the oral route (gavage) has been performed at Harlan Laboratories Ltd. Alongside a 2 year carcinogenicity study of sodium fluoride, the data are sufficient to provide a qualitative understanding of the toxicological properties of disodium fluorophosphate without the need for further toxicity testing.  No NOAEL was identified in the study, but the results were sufficient to accurately describe the effects of disodium fluorophosphate as relating to the fluoride content. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

The study was performed between 06 May 2010 and 19 October 2010. The in-life phase of the study was conducted between 11 May 2010 (first day of treatment) and 28 June 2010 (final necropsy).

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Blackthorn, Bicester, Oxon, UK
- Age at study initiation: approximately twelve weeks old.
- Weight at study initiation: males weighed 307 to 370g, the females weighed 189 to 232g
- Housing: Initially, all animals were housed in groups of five in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding (Datesand Ltd., Cheshire, UK). During the mating phase, animals were transferred to polypropylene grid floor cages suspended over trays lined with absorbent paper on a one male: one female basis within each dose group. Following evidence of successful mating, the males were returned to their original cages. Mated females were housed individually during gestation and lactation, in solid floor polypropylene cages with stainless steel mesh lids and softwood flakes.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: seven days

ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 2°C
- Humidity: 55 ± 15%
- Air changes: at least fifteen air changes per hour
- Photoperiod: 12hrs dark / 12 hrs light

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: For the purpose of the study the test item was prepared at the appropriate concentrations as a solution in Distilled water

VEHICLE
- Concentration in vehicle: 0, 6, 14 and 30 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of Disodium fluorophosphate in the test item formulations was determined by ion chromatography (IC) using an external standard technique. The results indicate that the prepared formulations were within ± 6% of the nominal concentration (see table 1).

Duration of treatment / exposure:

Up to eight weeks (including a two week maturation phase, pairing, gestation and early lactation for females), at dose levels of 30, 70 and 150 mg/kg/day

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 30, 70, 150 mg/kg/day
Basis:

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

Chronological Sequence of Study
i) Groups of ten male and ten female animals were treated daily at the appropriate dose level throughout the study (except for females during parturition where applicable). The first day of dosing was designated as Day 1 of the study.


ii) Prior to the start of treatment and once weekly thereafter, all animals were observed for signs of functional/behavioural toxicity.

iii) On Day 15, animals were paired on a 1 male: 1 female basis within each dose group for a maximum of fourteen days.

iv) Following evidence of mating (designated as Day 0 post coitum) the males were returned to their original cages and females were transferred to individual cages.

v) On completion of mating (during Week 6), five selected males per dose group were evaluated for functional/sensory responses to various stimuli.

vi) Pregnant females were allowed to give birth and maintain their offspring until Day 5 post partum. Evaluation of each litter size, litter weight, mean offspring weight by sex, clinical observations and landmark developmental signs were also performed during this period.

vii) At Day 4 post partum, five selected females per dose group were evaluated for functional/sensory responses to various stimuli.

viii) Blood samples were taken from five males from each dose group for haematological and blood chemical assessments on Day 42. Following completion of the female gestation and lactation phases, the male dose groups were killed and examined macroscopically.


ix) Blood samples were taken from five randomly selected females from each dose group at termination for haematological and blood chemical assessment on Day 4 post partum. At Day 5 post partum, all surviving females and surviving offspring were killed and examined macroscopically.

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were examined for overt signs of toxicity, ill-health and behavioural change immediately before dosing, up to thirty minutes after dosing, and one and five hours after dosing, during the working week. Animals were observed immediately before dosing soon after dosing, and one hour after dosing at weekends and public holidays

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on Day 1 (prior to dosing) and then weekly for males until termination and weekly for females until mating was evident. Body weights were then recorded for females on Days 0, 7, 14 and 20 post coitum, and on Days 1 and 4 post partum.


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: Measured daily throughout the study


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 42 for males and Day 4 post partum for females
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: five males and five females selected from each test and control group
- Parameters examined: Haemoglobin (Hb), Erythrocyte count (RBC), Haematocrit (Hct), mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), Total leucocyte count (WBC), Platelet count (PLT), Reticulocyte count (Retic) Prothrombin time (CT) was assessed by ‘Innovin’ and Activated partial thromboplastin time (APTT) was assessed by ‘Actin FS’ using samples collected into sodium citrate solution (0.11 mol/l).


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Day 42 for males and Day 4 post partum for females
- Animals fasted: No
- How many animals: five males and five females selected from each test and control group
- Parameters examined: Urea Calcium (Ca++), Glucose Inorganic phosphorus (P), Total protein (Tot.Prot.), Aspartate aminotransferase (ASAT), Albumin Alanine aminotransferase (ALAT), Albumin/Globulin (A/G) ratio (by calculation), Alkaline phosphatase (AP), Sodium (Na+), Creatinine (Creat), Potassium (K+), Total cholesterol (Chol), Chloride (Cl-), Total bilirubin (Bili), Bile acids (Bile)


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to termination
- Dose groups that were examined: five selected males and females from each dose level
- Battery of functions tested: sensory activity, grip strength and motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Data for males and females prior to pairing, and functional performance test data, where appropriate, quantitative data were analysed by the Provantis™ Tables and Statistics Module. For each variable, the most suitable transformation of the data was found, the use of possible covariates checked and the homogeneity of means assessed using ANOVA and ANCOVA and Barletts’s test. The transformed data were analysed to find the lowest treatment level that showed a significant effect, using the Williams Test for parametric data or the Shirley Test for non-parametric data. If no dose response was found, but the data showed non-homogeneity of means, the data were analysed by a stepwise Dunnett (parametric) or Steel (non-parametric) test to determine significant differences from the control group. Finally, if required, pair-wise tests were performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric). Data for females during gestation and lactation, and offspring data were assessed for dose response relationships by linear regression analysis, followed by one way analysis of variance (ANOVA) incorporating Levene’s test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett’s test. Where Levene’s test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney ‘U’ test. Non-parametric methods were used to analyse implantation loss, offspring sex ratio and landmark developmental markers.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

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

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
One male treated with 150 mg/kg/day was killed in extremis on Day 7. Two females from this treatment group were killed in extremis prior to littering on Day 42 and a further female from this treatment group was killed in extremis prior to littering on Day 49. The cause of the moribund condition could not be established histopathologically There were no further unscheduled deaths.

Increased salivation was detected in animals of either sex treated with 150 mg/kg/day from Day 9 (males) and Day 22 (females) onwards. An isolated incident of staining around the mouth was evident in one male treated with 150 mg/kg/day on Day 15 and staining around the snout was also evident in two males from this treatment group between Days 29 and 32. Observations at 70 mg/kg/day were confined to increased salivation in males from Day 15 onwards, staining around the mouth in two males on Days 29 and 30 and noisy respiration in one male and one female between Days 30 and 42. The animals treated with 150 mg/kg/day that were killed in extremis showed either a decreased respiratory rate, ptosis, pilo-erection, lethargy, hypothermia, hunched posture dehydration, fur staining, pallor of the extremities, tiptoe gait and/or increased salivation prior to termination. No such effects were detected in animals of either sex treated with 30 mg/kg/day.


BODY WEIGHT AND WEIGHT GAIN
Animals of either sex treated with 150 mg/kg/day showed a reduction in body weight gain during the first week of maturation with actual body weight losses being evident in four males and six females. Recovery in body weight gain was evident in males throughout the remaining treatment period however a reduction in body weight gain was evident in females from this treatment group during the final week of gestation and during lactation. Three females treated with 150 mg/kg/day showed actual body weight losses during lactation. Statistical analysis did not however reveal any significant intergroup differences during maturation, gestation or lactation. No such effects were detected in animals of either sex treated with 70 or 30 mg/kg/day. Males treated with 150 mg/kg/day showed a statistically significant increase in body weight gain during the final week of treatment however an increase in body weight gain is considered not to be of toxicological significance.

FOOD CONSUMPTION AND COMPOUND INTAKE
No adverse effect on food consumption was detected for males during the treatment period or for females during the pre-mating, gestation or lactation phases of the study

FOOD EFFICIENCY
Food efficiency was however reduced during the first week of treatment for animals of either sex treated with 150 mg/kg/day. Food efficiency for these animals was comparable to controls thereafter.

WATER CONSUMPTION AND COMPOUND INTAKE
Animals of either sex treated with 150 mg/kg/day showed an increase in overall water consumption throughout the treatment period. Statistical significance was achieved throughout gestation (p<0.01-0.001) and lactation (p<0.05-0.01) No such effects were detected in animals of either sex treated with 70 or 30 mg/kg/day


HAEMATOLOGY
Males treated with 150 mg/kg/day showed a statistically significant increase in neutrophil count (p<0.05). No toxicologically significant effects were detected in females treated with 150 mg/kg/day or animals of either sex treated with 70 or 30 mg/kg/day. Females treated with 150 mg/kg/day showed a statistically significant increase in platelet count, eosinophils and mean cell volume. The effect on eosinophils also extended to 70 mg/kg/day females. Males treated with 150 and 70 mg/kg/day showed a statistically significant increase in platelet count. The majority of individual values were within the normal range for rats of the strain and age used and were considered not to be of toxicological importance.

CLINICAL CHEMISTRY
Animals of either sex treated with 150 mg/kg/day showed a reduction in plasma chloride concentration (p<0.05-0.01) and an increase in inorganic phosphorus (p<0.01). Males treated with 150 mg/kg/day also showed an increase in calcium concentration (p<0.05), cholesterol (p<0.01) and a reduction in bilirubin (p<0.05) whilst females from this treatment group also showed an increase in urea (p<0.01), aspartate aminotransferase (p<0.01), alanine aminotransferase (p<0.01) and creatinine (p<0.05). The effect on alanine aminotransferase also extended to females treated with 70 mg/kg/day (P<0.01). No toxicologically significant effects were detected in males treated with 70 mg/kg/day or in animals of either sex treated with 30 mg/kg/day. Males from all treatment groups showed a statistically significant increase in albumin/globulin ratio. Males treated with 70 and 30 mg/kg/day also showed a statistically significant reduction in potassium concentration. All individual values were within the normal ranges for rats of the strain and age used and in the absence of a true dose related response the intergroup differences were considered of no toxicological importance. Females treated with 150 mg/kg/day showed a statistically significant reduction in alkaline phosphatase. All individual values were within the normal ranges for rats of the strain and age used and a reduction in this enzyme is not considered to be of toxicological significance.


NEUROBEHAVIOUR
Weekly open field arena observations did not reveal any treatment-related effects for treated animals when compared to controls. There were no toxicologically significant changes in functional performance. Males treated with 150 mg/kg/day showed a statistically significant increase in mean hind limb grip strength. This intergroup difference was confined to one out of the three tests and in the absence of any supporting clinical observations to suggest an effect of neurotoxicity, the finding was considered to be of no toxicological significance. Females treated with 150 mg/kg/day showed a statistically significant reduction in overall mobile activity. In the absence of any supporting clinical observations to suggest a neurotoxic effect, the intergroup difference was considered to be of no toxicological significance. Females treated with 150 and 70 mg/kg/day showed a statistically significant increase in mean fore limb grip strength whilst females from all treatment groups also showed a statistically significant reduction in overall motory activity. In the absence of a true dose related response the intergroup differences were considered to be of no toxicological importance. There were no treatment-related changes in sensory reactivity


ORGAN WEIGHTS
Animals of either sex treated with 150 mg/kg/day showed a statistically significant increase in kidney weight (p<0.05-0.01) both absolute and relative to terminal body weight. Males treated with 150 mg/kg/day also showed a statistically significant increase in liver weight both absolute and relative to terminal body weight. No toxicologically significant effects were detected in animals of either sex treated with 70 or 30 mg/kg/day. Females from all treatment groups showed statistically significant reductions in thymus weight and statistically significant increases in spleen weight both absolute and relative
to terminal body weight. Males treated with 150 and 70 mg/kg/day showed statistically significant reductions in prostate weight both absolute and relative to terminal body weight. In the absence of a true dose related response or any histology correlates the intergroup differences were considered to be of no toxicological significance. Females treated with 150 mg/kg/day showed a statistically significant increase in ovary weight both absolute and relative to terminal body weight. Males treated with 150 mg/kg/day showed a statistically significant reduction in absolute and relative semincal vesicle weight and a statistically significant increase in absolute and relative brain weight. Males treated with 70 mg/kg/day also showed a statistically significant increase in absolute and relative brain weight whilst males treated with 30 mg/kg/day showed a statistically significant reduction in absolute and relative thyroid/parathyroid weight. In the absence of any histology correlates the intergroup differences were considered to be of no toxicological importance.


GROSS PATHOLOGY
Offspring: Neither the incidence, type or distribution of macroscopic findings observed at necropsy of decendent offspring nor offspring killed at scheduled termination (Day 5 of age) indicated any adverse effect of maternal treatment.
Adults: Five males treated with 150 mg/kg/day showed a raised limiting ridge at necropsy and a thickened glandular region of the stomach. In addition, one male also showed enlarged cervical lymph nodes, one male also showed small seminal vesicles, pale and enlarged kidneys and pale adrenals and two males also showed a reddened glandular region of the stomach. A further male treated with 150 mg/kg/day showed pale adrenals and enlarged, pale and mottled kidneys. One female treated with 150 mg/kg/day showed pale adrenals and enlarged and pale kidneys. The male treated with 150 mg/kg/day that was killed in extremis showed a raised limiting ridge, reddened lungs, enlarged and pale kidneys together with hydronephrosis and a dark liver. The females from this treatment group that were killed in extremis showed enlarged and pale adrenals, pale and/or enlarged kidneys, either a pale liver, pale and reddened lungs, dark red contents in the stomach, a distended stomach, a raised limiting ridge, a pale glandular and/or non glandular region of the stomach or a red duodenum.ridge, a pale glandular and/or non glandular region of the stomach or a red duodenum. Two females treated with 70 mg/kg/day had sloughing on the glandular region of the
stomach. One of these females also showed enlarged lymph nodes. One female from this treatment group had a mottled liver and dark foci on the lungs and a further female from this treatment group had hydronephrosis in the right kidney. Seven males treated with 70 mg/kg/day and three males treated with 30 mg/kg/day showed a raised limiting ridge of the stomach at necropsy. One of these males from each treatment group also showed a thickened glandular region of the stomach. One control male had hydronephrosis in the right kidney and a further control male had a mass on the caudate lobe of the liver. In the absence of treatment these findings were of no toxicological significance.



HISTOPATHOLOGY: NON-NEOPLASTIC
The following treatment-related microscopic findings were detected:
Stomach: Hyperkeratosis and acanthosis, mainly at the limiting ridge, was evident in animals of either sex from all treatment groups. Parietal cell hypertrophy in the glandular mucosa was evident in animals of either sex treated with 150 and 70 mg/kg/day and in males treated with 30 mg/kg/day. Submucosal inflammation was also noted in males from all treatment groups. Glandular erosion of the stomach was noted in two males treated with 150 mg/kg/day and two females from this treatment group also showed superficial desquamation of the glandular surface.

Kidneys: Tubular degeneration and tubular simple dilation was noted in animals of either sex treated with 150 mg/kg/day and in males treated with 70 mg/kg/day. Granulocytic casts and interstitial nephritis were also evident in animals of either sex treated with 150 mg/kg/day

Submaxillary Gland: Acinar cell atrophy was evident in four males and two females treated with 150 mg/kg/day and one female treated with 70 mg/kg/day.

Pancreas: Acinar cell atrophy was evident in one male and six females treated with 150 mg/kg/day and in one female treated with 70 mg/kg/day. Fibrosis was also noted in three females treated with 150 mg/kg/day.

Mammary Gland: Acinar atrophy was evident in six males treated with 150 mg/kg/day, two males treated with 70 mg/kg/day and one male treated with 30 mg/kg/day.

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Dose descriptor:

LOAEL

Effect level:

30 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects; gross pathology; histopathology;

Critical effects observed:

not specified

Table 1: Verification of Concentration of Test Item Formulations

Analysis number	Nominal concentration (mg/ml)	Concentration found
		(mg/ml)	(expressed as % of nominal)
1	0 6 14 30	ND 5.88 13.8 30.0	- 98 98 100
2	0 6 14 30	ND 5.72 14.1 29.8	- 95 101 99
3	0 6 14 30	ND 6.18 14.4 31.0	- 103 103 103
4	0 6 14 30	ND 5.62 14.7 30.0	- 94 105 100

Conclusions:

The oral administration of Disodium fluorophosphate to rats by gavage, at dose levels of 30, 70 and 150 mg/kg/day, resulted in treatment-related effects at all dose levels. A ‘No Observed Effect Level’ (NOEL) for systemic toxicity has therefore not been established.
Although this study is not sufficient to fulfil the information requirements for sub-chronic repeated dose toxicity, the study provides enough reliable data to conclude that the leading health effects of disodium fluorophosphate are as a result of the fluorine present in the substance. As the health effects of inorganic fluorides are well defined (see supporting data and endpoint summary), further in vivo testing on disodium fluorophosphate is not considered to be scientifically justified as a widely recognised OEL of 2.5 mg/m3 F is available for inorganic fluorine.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

A weight of evidence approach consisting of Klimisch reliabilty 1 data on disodium fluorophosphate and Klimisch reliability 2 data on sodium fluoride is presented.

Additional information

Justification of choice of data to be used in the Chemical Safety Report:

A repeat dose toxicity study with reproduction/developmental toxicity screening test in the rat (OECD Method 422, 28-days) via the oral route (gavage) has been performed at Harlan Laboratories Ltd. The results of the study indicated that the leading health effects were as a result of the effects of fluoride intake (fluorosis). Some evidence of phosphate-induced nephritis was also observed but is considered to occur at higher dose levels than the effects of fluorides (effects were noted at 150 mg/kg bw/day). In addition,Phosphate is an essential element; a maximum tolerable daily intake value (MTDI) for phosphates is reported to be 70 mg/kg bw/day. This dose level exceeds the restrictions placed on inorganic fluorides.

The following weight of evidence data has been included to provide comparative evidence of the effects of fluoride in the substance sodium fluoride (sodium fluoride contains approximately 47% F compared to 13% F in disodium fluorophosphate).

 

Data available on sodium fluoride:

Subchronic Toxicity:

The U.S. National Toxicology Program (NTP, 1990) evaluated the toxicological effects of continuous exposure to 0, 30, 100 or 300 ppm sodium fluoride in drinking water on F344 male and female rats for a 6-month period. Sodium fluoride caused weight loss at 300 ppm, fluorosis of the teeth at 100 and 300 ppm, minimal hyperplasia of the gastric mucosa of the stomach at 100 and 300 ppm (however, one high dose rat of each sex had an ulcer), a dose-related increase in fluoride content of bone and urine with increasing fluoride concentration in the drinking water, and a significant increase in fluoride content in the plasma at 300 ppm. No significant signs of toxicity were observed at concentrations of 10 or 30 ppm.

The U.S. National Toxicology Program (NTP, 1990) evaluated the toxicological effects of continuous exposure to 0, 10, 50, 100, 200, 300 or 600 ppm sodium fluoride in drinking water of male and female B6C3F1 mice for a 6-month period. Sodium fluoride caused death in some animals at 600 ppm and in a single male animal at 300 ppm, weight loss at 200 to 600 ppm, fluorosis of the teeth at 100, 200, 300 and 600 ppm, acute nephrosis and/or lesions in the liver and myocardium in mice that died early, minimal alterations in bone growth/remodeling in the long bones at 50 to 600 ppm, a dose-related increase in fluoride content of bone and urine with increasing fluoride concentration in the drinking water, and a possible dose-related increase in fluoride content in the plasma. No signs of toxicity were observed at the low dose of 10 ppm sodium fluoride.

Chronic Toxicity

The U.S. National Toxicology Program (NTP, 1990) evaluated the toxicological and carcinogenic effects of continuous exposure to 0, 25, 100 or 175 ppm sodium fluoride in drinking water on male and female F344/N rats for a 2 -year period. Survival and weight gains of the male and female rats were not affected by fluoride treatment. Rats receiving sodium fluoride developed effects typical of dental fluorosis at 25, 100 and 175 ppm, and female rats had increased osteosclerosis at the high-dose of 175 ppm.

As the effects of inorganic fluorides have been extensively studied, it is therefore not considered to be ethically sound to investigate the effects of disodium fluorophosphate further. To this end it is recommended that the exposure limit for inorganic fluorides (NIOSH, UK HSE) is observed and

is used in the risk assessment in place of a DNEL. The OEL is 2.5 mg F/m³. This value is considered to be low enough to be protective of any potential effects.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study is most representative of the substance to be registered.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach; glandular: mammary gland

Justification for classification or non-classification

Data available is not sufficient to result in a classification for STOT-RE.