Lithium phosphorodifluoridate

Endpoint summary

Description of key information

In an GLP-compliant study conducted in accordance with a standard method equivalent to the OECD guideline, the repeated dose toxicity to rats via the oral route was assessed over a 28-day period. Mortality and treatment-related effects were observed in the stomach and kidney in the highest dose tested (40 mg/kg/day) in both male and female rats. Treatment-related effects were also observed in the stomach at the middle dose treated (8 mg/kg/day) in males although minimal and considered not adverse. For the purpose of the Chemical Safety Assessment, the lowest NOAEL determined from this study (8 mg/kg/day - males/females) was conservatively selected.

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:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Qualifier:

according to guideline

Guideline:

other:

Version / remarks:

Testing Method Concerning New Chemical Substances
(Notification No. 1121002, PFSB, MHLW; No. 2 of November 13, 2003, MIB, METI;
No. 031121002, EPB, MOE; dated November 21, 2003)

Principles of method if other than guideline:

The purpose of this study was to assess the toxic effects of LiPO2F2 and its reversibility by observing functional and morphological changes after a 28-day repeated oral administration of LiPO2F2 to rats.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

CRl:CD(SD)

Details on species / strain selection:

This strain is widely used in toxicity studies using rodents, and there is plenty of historical data and a large number of animals are available.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Females: nulliparous and non-pregnant: yes
- Age at study initiation: 5 weeks old
- Weight at study initiation: 162 to 186g (males); 128 to 157g (females)
- Fasting period before study: no
- Housing: Hanging type stainless-steel wire mesh cages (195W × 325D × 180H mm) sterilized by autoclave were used and replaced on the day of grouping and once every 14 days after the start of administration. Aluminum trays sterilized by autoclave were used and replaced on the day of grouping and once every 7 days after the start of administration. Hardwood chips for experimental animals (Beta-Chip®) were placed on the trays and were replaced at the same time as the trays.
- Diet (e.g. ad libitum): Diet was given ad libitum except during the measurement of motor activity and fresh urine collection and replaced at the same time as the feeders. The animals were fasted from the evening before the scheduled necropsy (about 20 to 23 hours).
- Water (e.g. ad libitum): Water was given ad libitum except during the measurement of motor activity and fresh urine collection. The water was replaced at the same time as the watering bottles.
- Acclimation period: 7 days, animals observed daily with respect to health conditions during this period

DETAILS OF FOOD AND WATER QUALITY:
Analysis data by Japan Food Research Laboratories were obtained from the food supplier. On the basis of the analysis data, it was confirmed that the levels of the contaminants, such as residual pesticides in the lots used met the specification of the Standard Operating Procedure at the testing facility.
Tap water is periodically analyzed (twice a year) by Dia Analysis Service Inc. From the analytical data, it was confirmed that the quality of the water met the specifications of the Standard Operating Procedure of the testing facility.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.8 - 23.2°C
- Humidity (%): 37.8 to 60.9
- Air changes (per hr): 6 to 20 changes per hour with all fresh filtered air
- Photoperiod (hrs dark / hrs light): 12 hours per day (7:00 to 19:00)

Route of administration:

oral: gavage

Details on route of administration:

The animals were administered by gavage using a gastric tube with a disposable syringe.
The dosing suspensions were stirred with a magnetic stirrer before dosing.

Vehicle:

olive oil

Details on oral exposure:

- PREPARATION OF DOSING SOLUTIONS:
Dosing suspensions were prepared under UV cut-off fluorescent light. The test substance was weighed in the glove box where air was replaced with nitrogen gas, and the relative humidity was confirmed to be below 30% with a hygrometer (actual
value: 18.5% to 28.5%).
The frequency of preparation of 0.8 and 4 mg/mL dosing suspensions was once every 7 days according to the results of a stability analysis conducted at the outsourcing site. The 0.16 mg/mL dosing suspension was prepared just before use. Dosing suspensions after preparation were divided into a polypropylene tube for each dosing day and were stored refrigerated (actual value: 3.6° to 5.9°C, permissible range: 1° to 10°C), in a dark place filled with nitrogen gas.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test substance in dosing suspensions at concentrations of 0.4, 4, and 100 mg/mL was confirmed to be stable under refrigeration, in a dark place filled with nitrogen gas for 8 days.

At the first preparation, the sampling dosing suspensions (n=3) from 3 points (upper, middle, and bottom layers) of the 0.8 and 4 mg/mL dosing suspensions were sent to the outsourcing site and confirmed for concentrations (actual value: 102.5%, within ±10% of the nominal concentration) and their homogeneity (actual value: 2.0% to 3.9%, C.V. of the upper, middle and bottom layers, within ±10%). As for the 0.16 mg/mL dosing suspension, the 0.8 mg/mL dosing suspension of the initial preparation was sent separately to the site. Then suspension, which was diluted with the vehicle (just before analysis for concentrations and homogeneity), was sampled and confirmed for concentrations (actual value: 100.0%, within ±10% of the nominal concentration) and their homogeneity (actual value: 5.4%, C.V. of the upper, middle, and bottom layers, within ±10%). The dosing suspensions were sent to the outsourcing under refrigeration, in a dark place filled with nitrogen gas (replacing the air in the storage bottle with nitrogen gas).

Method of analysis: Ion Chromatography

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once daily, the dose volume was set at 10 mL/kg, and the individual dose was calculated on the basis of the most recently measured body weights.

Dose / conc.:

1.6 mg/kg bw/day (nominal)

Remarks:

Low dose

Dose / conc.:

8 mg/kg bw/day (nominal)

Remarks:

Middle dose

Dose / conc.:

40 mg/kg bw/day (nominal)

Remarks:

High dose

No. of animals per sex per dose:

Control = 10 male, 10 female
1.6 mg/kg = 5 male, 5 female
8 mg/kg = 5 male, 5 female
40 mg/kg = 10 male, 10 female

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
Dose levels were set based on the results in a dose range finding study (7-day repeated dose oral toxicity study): dose levels: 0, 20, 100 and 500 mg/kg, 5 animals/sex/group performed at the testing facility.
Death occurred by Day 7 in 3 males and 4 females in the 100 mg/kg group and 5 males and 5 females in the 500 mg/kg group. In consideration of the incidence of death, 100 and 500 mg/kg were not judged to be suitable for the main study therefore, the administration was terminated on Day 7, and all the animals were subjected to necropsy. The following changes were observed in the animals that had died: decrease in locomotor activity in both sexes in the 100 and 500 mg/kg groups, salivation in males in the
100 mg/kg group and females in the 500 mg/kg group, smudge of perinasal area in males in the 100 mg/kg group, prone position in females in the 100 and 500 mg/kg groups, hunchback position in females in the 100 mg/kg group. Also, hunchback position was
observed in the surviving females in the 100 mg/kg group. As a result of necropsy, the following changes were observed in the dead animals and surviving animals in the 100 mg/kg group: dark reddish change in the mucosa of the glandular stomach in both
sexes in the 100 and 500 mg/kg groups, thickening of limiting ridge in the stomach in both sexes in the 100 mg/kg group, dilation of the stomach in both sexes in the 500 mg/kg group, dark reddish change in the mucosa of the ileum in males in the 500 mg/kg group, red abnormal contents in the duodenum to ileum and in the ileum in females in the 100 mg/kg group, dark reddish change in the mucosa of the duodenum to ileum and in the mucosa of ileum in females in the 500 mg/kg group, small spleen, thymus, seminal vesicle, and prostate in males or females in the 100 mg/kg group, dark reddish change of partial lobe in the lungs in females in the 500 mg/kg group. In the 20 mg/kg group, increased adrenal weight was noted in males only. From the above results, death occurred in the 100 mg/kg group, while no clear toxicity change was found in the 20 mg/kg group. Accordingly, the highest dose for this study was set at 40 mg/kg, at which certain toxicity change was expected to be seen, and middle and low dose levels were set at 8 and 1.6 mg/kg, respectively, with a common ratio of 5. Additionally, a control group (0 mg/kg) receiving the vehicle (olive oil) alone was also established.

- Rationale for animal assignment (if not random):
All animals were confirmed to be in good health based on the results of the observation for clinical signs and body weights during the quarantine/acclimation period. Animals were assigned to groups 2 days before the start of administration by the
stratified-by-weight randomization method so that they were evenly assigned with respect to the mean body weight.

- Post-exposure recovery period:
A 14-day recovery period was established for 5 males and 5 females each in the control, 8, and 40 mg/kg groups upon completion of the dosing period.

Positive control:

Not applicable

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day during exposure period (before and after dosing), once per day (in morning) during recovery

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were examined once before the start of administration and once a week in the afternoon (following the observation after administration) during the dosing period. Hand-held observations and open field observations for a 2-min period were performed.
- Observations checked in table 1 were included.

BODY WEIGHT: Yes
- Time schedule for examinations:
All animals were weighed on Days 1, 8, 15, 22, and 28 during the dosing period and on Days 29, 36, and 42 during the recovery period using an electronic balance. The dead animal was measured upon discovery. The measurements during the dosing period were conducted before dosing.

FOOD CONSUMPTION: Yes
- 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: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: Non detailed observations made as part of the clinical checks (e.g. pupil size, palpebral closure etc.).

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 29 and Day 43
- Anaesthetic used for blood collection: Yes (Nembutal®)
- Animals fasted: Yes
- How many animals: (20 animals - Day 29; 15 animals - Day 43)
- Parameters checked in table 2 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Day 29 and Day 43
- Animals fasted: Yes
- How many animals: (20 animals per sex - Day 29; 15 animals - Day 43 (females); 14 animals - Day 43 (males)
- Parameters checked in table 3 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: final week of dosing (Day 26)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (during sampling)
- Parameters checked in table 4 were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once in the final dosing week (Week 4) and recovery group (Week 6 - males only)
- Dose groups that were examined: All groups in Week 4; Control, 8 mg/kg and 40 mg/kg
- Battery of functions tested: sensory activity / grip strength / motor activity

IMMUNOLOGY: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 5)

HISTOPATHOLOGY: Yes (see table 6)

Statistics:

Numerical data of multiple groups were analyzed for their statistical significance by multiple comparison tests. Homogeneity of variance among the groups was first tested by Bartlett’s test. If the group variance was determined to be homogeneous, all groups were compared by one-way analysis variance. If Bartlett’s test indicated heterogeneous variance, Kruskal-Wallis test was employed, and Dunnett (if homogeneous) or Dunnett type (if heterogeneous) multiple comparison test was used when there was a significant difference between the groups. The categorical data of multiple groups concerning the urinalysis were analyzed by Kruskal-Wallis test. Dunnett type multiple comparison test was used when there was a significant difference between the groups. The categorical data of histopathology were analyzed by Wilcoxon’s rank sum test for each finding between the control and each treatment group.

The significant level of 5% was set for Bartlett’s test, one-way analysis variance, and Kruskal-Wallis test. The significant levels of 1 and 5% were set for the other analyses. Toxicological Data Processing System (MiTOX®, Mitsui Zosen Systems Research Inc.) was used for analyses.

Statistical analysis was performed on items listed below. The analysis was not performed on clinical signs, detailed clinical observations (except for rearing), function tests (approach response, touch response, auditory response, tail pinch response, aerial righting reaction), or necropsy findings.
[Numerical data]
Detailed clinical observation (rearing), function tests (grip strength of fore and hind limb, motor activity), body weights, food consumption, hematology, blood chemistry, Urinalysis (urine volume, specific gravity, Na, K, Cl, water consumption), absolute organ weights, relative organ weights
[Categorical data]
Urinalysis (pH, protein, glucose, ketones, occult blood, urine sediments),
histopathological examination

Clinical signs:

no effects observed

Description (incidence and severity):

In the surviving animals, salivation was observed after dosing in both sexes of the 40 mg/kg group. Salivation was noted on Day 11 or later for males and on Day 4 or later for females; however all was expressed just after dosing and disappeared by 1.5
hours after dosing, and transient. No abnormality was noted in either sex in the 1.6 or 8 mg/kg group.

No abnormalities were observed in either sex of any groups in hand-held observations or open field observations, and no significant changes were observed in rearing either.

Mortality:

mortality observed, treatment-related

Description (incidence):

One male in the 40 mg/kg group died before dosing on Day 20. This animal showed smudge of perinasal area from Day 19, and smudges of perioral and perineal regions at death. In addition, salivation was observed after dosing on Day 10 or
later.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreased body weights or a tendency toward decreased body weights were observed on Days 22 and 28 in males of the 40 mg/kg group. Decreased body weights were continuously observed during the recovery period. One female (No. 50407) in the
40 mg/kg group showed decreased body weights on Day 28 though there was no significant change. However, the body weight in this animal shifted to increase by Day 36 during recovery period, and recovered comparable with the control group.
No significant changes were noted in either sex in the 1.6 or 8 mg/kg group throughout the dosing or recovery periods.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Decreased food consumption was observed on Day 26 in males of the 40 mg/kg group, while food consumption during the recovery period was comparable with the control group. One female in the 40 mg/kg group in which body weight was decreased, showed decreased food consumption on Day 26 (-7 g from previous value) compared to the other animals. During the recovery period, however, the food consumption in this animal increased more than that of the control group.
No significant changes were noted in either sex in the 1.6 or 8 mg/kg group throughout the dosing or recovery periods.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The following changes were observed in the 40 mg/kg group: increased leukocyte counts or a tendency toward increased leukocyte counts in both sexes, increased platelet count, a tendency toward decreased reticulocyte count, a tendency toward decreased lymphocyte ratios, a tendency toward increased neutrophil ratio in males, increased reticulocyte ratio in females. Also, the decreased lymphocyte ratio and increased neutrophil ratio were observed in 2 females (Nos. 50402 and 50405). At the end of recovery period, these changes were not observed and there were no significant changes in any parameters of either sex. No significant changes were noted in any parameters of either sex in the 1.6 or 8 mg/kg group.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

[At the end of the dosing period]
The following changes were observed in the 40 mg/kg group: increased γGT, creatinine, and inorganic phosphorus, decreased albumin, a tendency toward increased ALAT and urea nitrogen in males, increased triglyceride and a tendency toward increased triglyceride in both sexes.
Other than the above, a tendency for increased for ASAT and total cholesterol was observed in males of the 40 mg/kg group. However, these changes were considered to be toxicologically insignificant, since they were within mean±2 S.D. of the historical data of the testing facility
[At the end of the recovery period]
Increased inorganic phosphorus was observed in males of the 40 mg/kg group. Decreased ALAT in males and decreased K in females of the 40 mg/kg group, and decreased ASAT in females of the 8 and 40 mg/kg groups: however, these changes were considered to be toxicologically insignificant by the following reasons: they were not noted at the end of the dosing period, values for ASAT and ALAT were opposite changes to toxicologically significant high values, all individual values for K were within mean±2 S.D. of the historical data of the testing facility.
Although increased total protein was observed in females of the 8 mg/kg group, it was considered to be incidental since no correlation with dose levels was detected.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

[Dosing period]
In the qualitative analysis, decreased pH and ketones for males and a tendency toward decreased total protein for both sexes were observed in the 40 mg/kg group. In the examination of urine sediments, increased epithelial cell and a tendency toward increased cast were observed in males of the 40 mg/kg group. Epithelial cell and cast were also observed in 1 female. In the quantitative analysis, increased urine volume and water consumption for both sexes and decreased specific gravity for males were observed in the 40 mg/kg group.
Other than the above, increased water consumption was observed in females of the 1.6 mg/kg group; however, it was considered to be incidental since no correlation with dose levels was detected and there were no changes in the other parameters.

[Recovery period]
In the qualitative analysis, a tendency toward decreased ketones for both sexes and a tendency toward decreased total protein for females were observed in the 40 mg/kg group. In the examination of urine sediments, epithelial cell was observed in 1 male and 1 female of the 40 mg/kg group. Epithelial cell was also observed in one female in the 8 mg/kg group; however, this change was considered to be toxicologically significant since similar change was not noted during the dosing period, and there was no abnormality in the kidney in the histopathological findings.
Other than the above, in the quantitative analysis, decreased Na was observed in females of the 40 mg/kg group; however, it was considered to be toxicologically significant since similar change was not noted during the dosing period, and there were no changes attributed to the test substance in any other parameters.

Behaviour (functional findings):

effects observed, non-treatment-related

Description (incidence and severity):

In motor activity measurements, the motor activity decreased between 20 and 40 minutes and in total in males of the 40 mg/kg group. At the measurement of recovery period, the motor activity increased between 10 and 20 minutes in males of the 8 and 40 mg/kg groups. However, this change was considered to be toxicologically insignificant, since the similar changes were not observed in the measurement of dosing period, and there was no significant change in total motor activity when compared to the control group and it showed normal motor pattern. Sensory reactivity to stimuli was comparable in both sexes of all groups, and no abnormalities were noted. Grip strength measurements revealed no significant changes either.Therefore,
the decreases in motor activity were not considered attributable to neurotoxicity of the test substance, but to the secondary changes associated with aggravated physical condition of the animals.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Increased relative weights of kidney, liver and adrenal were observed in males, females and both sexes in the 40 mg/kg group, respectively.
Other than the above, decreased absolute weight and increased relative weight in the brain and decreased absolute spleen weight were observed in males of the 40 mg/kg group.
However, the both changes were considered attribute to the decreased body weights since the absolute and relative weights were opposite changes for the brain and it was only
unilateral change for the spleen. At the end of the recovery period, the above changes were not observed, nor were there no significant changes in any parameters of either sex between control and test substance treatment groups.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

[Dead animal]
There were neither findings related to cause of death nor macroscopic abnormalities in the dead animal.

[Animals for necropsy after dosing period]
As a change attribute to the test substance, 1 male showed yellowish patch in the kidney in the 40 mg/kg group.
Other than the above, small thyroid (unilateral) and small testis (unilateral) were observed in 1 male of the 1.6 mg/kg group and 1 male of the 8 mg/kg group, respectively. These changes were considered to be incidental due to their circumstances of expression.
[Animals for necropsy after recovery period]
One female in the 8 mg/kg group showed small thyroid (unilateral), but it was considered to be incidental due to the circumstance of expression. In the control group, reddish change of a part of lobe in the liver was observed in 1 female.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

[Dead animal]
As changes attributed to the test substance, there were degeneration/necrosis of tubule (mild) and basophilic tubule (minimal) in the kidneys, increase of karyorrhexis (mild) in the mandibular and mesenteric lymph nodes, acute atrophy of the thymus (mild), atrophy of the spleen (mild), and massive necrosis of the cortex adrenal (moderate) in the dead animal of the 40 mg/kg group.

[Animals for necropsy after dosing period]
Changes attributed to the test substance were observed in the stomach and kidney of the both sexes.The findings observed in the stomach were as follows: eosinophilic infiltration in the submucosa in 1 male of the 8 mg/kg group (minimal), and 4 males (minimal) and 4 females (minimal) in the 40 mg/kg group; hyperplasia of foveola gastrica in the glandular stomach in 5 males and 5 females (minimal) in the 40 mg/kg group; hyperplasia of squamous in limiting ridge in 1 male of the 8 mg/kg group (minimal), and 4 males (minimal) and 5 females (minimal) in the 40 mg/kg group; increase of globule leukocyte in the glandular stomach in 1 male of the 8 mg/kg group (minimal), and 4 males (minimal) and 5 females (minimal) in the 40 mg/kg group.

The findings observed in the kidney were as follows: basophilic tubule in 5 males (mild) and 4 females (minimal: 3 females, mild: 1 female) in the 40 mg/kg group; dilation of tubule in 5 males (mild) and 2 females (minimal) in the 40 mg/kg group. Also, one male with yellowish patch in the kidney at the necropsy showed basophilic tubule.

Differently from above changes, focal basophilic tubule was occasionally observed in each group including the control group. However, this change is known to occur spontaneously as historical lesions and not attribute to the test substance.
In the findings observed at the necropsy, the small thymus (unilateral) in 1 male of the 1.6 mg/kg group was hypoplasia, and the small testis (unilateral) in 1 male the 8 mg/kg group was atrophy. Other than the above, various histopathological changes were observed in the examined animals of each group including the control group; however, these changes were considered not to be test substance-related because they are spontaneously observed in rats and there were no clear dose dependency.
[Animals for necropsy after recovery period]
In the kidney, basophilic tubule was observed in 2 males (minimal) and 3 females (minimal) of the 40 mg/kg group. In the stomach, however, no changes noted at the end of dosing period were observed in either sex.
In the findings observed at the necropsy, the small thyroid (unilateral) in 1 female of the 8 mg/kg group was hypoplasia. As for the reddish change of a part of lobe in the liver in 1 female of the control group, there was no appreciable histopathological finding. Other than the above, various histopathological changes were observed in the examined animals of each group including the control group; however, these changes were considered not to be test substance-related because they are spontaneously observed in rats and there were no clear dose dependency.

Histopathological findings: neoplastic:

not examined

Details on results:

In the animals for necropsy after the dosing period, there were minimal changes attribute to the test substance in the stomach of males of the 8 mg/kg group (not considered adverse as small number of animals affected and completely recovery observed), and the stomach and kidney of both sexes in the 40 mg/kg group (see table 7 - results)

Key result

Dose descriptor:

NOAEL

Effect level:

8 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical biochemistry

gross pathology

histopathology: non-neoplastic

mortality

urinalysis

Dose descriptor:

NOAEL

Effect level:

8 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical biochemistry

gross pathology

histopathology: non-neoplastic

urinalysis

Critical effects observed:

yes

Lowest effective dose / conc.:

40 mg/kg bw/day (nominal)

System:

gastrointestinal tract

Organ:

stomach

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Critical effects observed:

yes

Lowest effective dose / conc.:

40 mg/kg bw/day (nominal)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Table 7: Histopathological changes considered attributed and their appearances of expression

Sex		Male							Female
Fate		FS				RS			FS				RS
Dose level (mg/kg)		0	1.6	8	40	0	8	40	0	1.6	8	40	0	8	40
	Grade
		(5)	(5)	(5)	(5)	(5)	(5)	(4)	(5)	(5)	(5)	(5)	(5)	(5)	(5)
Stomach
Cell infiltration, eosinophil, glandular stomach	+	0	0	1	4	0	0	0	0	0	0	4	0	0	0
Hyperplasia, foveola, glandular stomach	+	0	0	0	5	0	0	0	0	0	0	5	0	0	0
Hyperplasia, squamous limiting ridge	+	0	0	1	4	0	0	0	0	0	0	5	0	0	0
Increase, globule leukocyte, glandular stomach	+	0	0	1	4	0	0	0	0	0	0	5	0	0	0
Kidney
Basophilic, tubule	+	0	0	0	0	0	0	2	0	0	0	3	0	0	3
	++	0	0	0	5	0	0	0	0	0	0	1	0	0	0
Dilatation, tubule	+	0	0	0	0	0	0	0	0	0	0	2	0	0	0
	++	0	0	0	5	0	0	0	0	0	0	0	0	0	0

Fate: FS, necropsy after dosing period; RS, necropsy after recovery period

Grade: +, minimal; ++, mild

( ): Number of examined animal

LiPO2F2 known as perfluoro inorganic lithium acid has hydroscopicity and possibly generate hydrogen fluoride in vivo. Hydrogen fluoride has extremely strong corrosive

properties against the skin and membrane, and LDL0 in rats via intraperitoneal administration has been reported to be 25 mg/kg [1]. Besides, results of a repeated dose inhalation toxicity study in rats indicated failures of the central nervous system (loss of conditioned reflex, prolonged latent time from stimulation to motorius reflex) and change in nerve synapse in general as well as degeneration and/or necrosis of the renal tubule at a lethal dose [2]. Similarly, stimulations and effects on the kidneys were also noted in this study; however, no changes indicative of neural toxicity were found.

[1] Hydrofluoric acid. In: Industry (expanded edition). Tokyko: Ishiyaku Pub, Inc; 1994.

p.24-25

[2] Hydrofluoric acid, Hazard Data Sheet for Chemical Substances, Reference No.

2001-46, Class Reference No. in the Gazette List 1-306 Standards for Testing

Facilities Implementing Studies of New Chemical Substances), 1-283 (Law for

Promotion of Chemical Management), CAS No. 7664-39-3

Conclusions:

Consequently, the no-observed-adverse-effect-level (NOAEL) of LiPO2F2 was considered to be 8 mg/kg /day for males and females under the conditions of this study.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

8 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

All toxicological studies on the test substance have been conducted in accordance to OECD (or equivalent) guideline and GLP-compliant. Therefore the quality of the database is regarded as high quality.

System:

other: Gastrointestinal tract and urinary system

Organ:

kidney

stomach

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the data available from the 28-day repeated dose toxicity study, effects seen in the stomach and kidneys of the animals tested should be considered for classification purposes. The NOAEL is determined at 8 mg/kg/day in male and females rats. Guidance values stated in the CLP regulation (EC 1272/2008, as amended) to assess specific target organ toxicity repeated dose (STOT RE) indicate that this study should be classified as STOT RE 1 (H372) based on extrapolating the NOAEL determined from a study with an exposure period of 28 days (10 mg/kg/day x 3 = 30 mg/kg/day). As the NOAEL for this study is 8 mg/kg/day which is much lower than the 30 mg/kg/day, this substance is classified as STOT RE 1 (H372) in accordance with the CLP regulation (EC 1272/2008, as amended). Target organs, kidney and stomach are also specified.