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Administrative data

Description of key information

There is one acceptable study report available on a 90-day study in rats performed with ammonium thiocyanate according to OECD408 and GLP. Mortality was observed at 500 mg/kg bw per day. At 100 mg/kg bw signs of toxicity include changes in haematological and clinical chemistry parameters. The NOAEL is 20 mg NH4SCN/kg bw/day. (Equal to 15.3 mg SCN-/kg bw/day)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 1999 - August 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to internationally accepted guidelines and GLP.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
equivalent or similar to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: ± 6 weeks
- Weight at study initiation: males week 1 mean: 209-212g, females week 1 mean: 166-171g
- Fasting period before study: not applicable, animals were fasted overnight before clinical laboratory investigations
- Housing: Group housing of 5 animals per sex per cage in stainless steel suspended cages with wire mesh floors
- Diet (e.g. ad libitum): ad libitum, standard pelleted laboratory animal diet (from Carfil Quality BVBA, Oud-Turnhout, Belgium)
- Water (e.g. ad libitum): ad libitum, tap-water
- Acclimation period: at least 5 days under laboratory condictions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 50
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: 26 May 1999 - 27 Augustus 1999
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations were placed on a magnetic stirrer during dosing, except for the first 17 days. This deviation was considered not to have affected study integrity.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Formulation analysis for accuracy of preparation was performed. The concentiations of ammonium thiocyanate in the used test media were analyzed by means of ion chromatography. The concentration of ammonium thiocyanate in the used test media was determined before and after the toxicity study by the General Analytical and Environmental Chemistry Department of Akzo Nobel Central Research. Random samples (approximately 10 ml) were taken from all formulations prepared on Days I and 90. Three series of samples for analysis were sent by Notox B.V.

Duration of treatment / exposure:
92-93 days
Frequency of treatment:
Once daily for at least 90 days, approximately the same time each day; 7 days per week.
Remarks:
Doses / Concentrations:
20, 100 , 500 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results of the 14-day range finding study in rats (NOTOX Project 260112).
- Rationale for animal assignment (if not random): At least 5 days before study start, by computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean.
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): no data
Positive control:
Not required.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once prior to start of treatment and at weekly intervals.
- Cage side observations: clinical signs

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-test and at week 13
- Dose groups that were examined: all animals and groups 1 and 3

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necrops, day 92 or 93
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes, overnight
- How many animals: all animals
- Parameters checked in table 1. were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necrops, day 92 or 93
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes, overnight
- How many animals: all animals
- Parameters checked in table 1. were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 12-13
- Dose groups that were examined: all animals
- Battery of functions tested:
- hearing ability
- pupillary reflex
- static righting reflex
- grip strength
- activity test
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All animals surviving to the end of the observation period and all moribund animals were deeply anaesthetised using ether vapour and subsequently exsanguinated. All animals were necropsied and descriptions of all macroscopic abnormalities were recorded. Samples of the following tissues and organs were collected from all animals at necropsy and fixed in neutral phosphate buffered 4% formaldehyde solution:

Identification marks: not processed
Adrenal glands
Aorta
Brain
Caecum
(Cervix)
(clitoral gland)
Colon
Duodenum
Epididymides
(Eyes with optic nerve and Harderian gland)
(Female mammary gland area)
(Femur including joint)
Heart
Ileum
Jejunum
Kidneys
(Larynx)
(Lacrimal gland, exorbital)
Liver
Lung, infused with formalin
Lymph nodes - mandibular, mesenteric
(Nasopharynx)
Oesophagus
Ovaries
Pancreas
Peyerk patches (jejunum, ileum) if detectable
Pituitary gland
(Preputial gland)
Prostate gland
Rectum
(Salivary glands - mandibular, sublingual)
Sciatic nerve
(Seminal vesicles)
(Skeletal muscle)
(Skin)
Spinal cord -cervical, midthoracic, lumbar
Spleen
Sternum with bone marrow
Stomach
Testes
Thymus
Thyroid including parathyroid
(Tongue)
Trachea
Urinary bladder
Uterus
(Vagina)
All gross lesions

HISTOPATHOLOGY: Yes

All organ and tissue samples, as defined under Histopathology (following), were processed, embedded and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin.
The following slides were examined by a pathologist:
- all tissues collected at the scheduled sacrifice from all animals of the control and the highest surviving dose group (i.e. Group 3)
- all tissues from all animals of all dose groups which died spontaneously or were terminated in extremis
- all gross lesions and lungs, liver and kidneys of all animals (all dose groups)

Based on treatment-related morphological changes in the stomach of the animals in the high dose group (i-e. Group 3), the histological examination was extended to that particular organ of all animals of Group 2. All abnormalities were described and included in the report. Tissues mentioned between brackets were not examined as there were no signs of toxicity or target organ involvement. An attempt was made to correlate gross observations with microscopic findings.
Other examinations:
ORGAN WEIGHTS
The following organ weights (and terminal body weight) were recorded from the surviving animals on the scheduled day of necropsy:
Adrenal glands
Brain
Epidid ymides
Heart
Kidneys
Liver
Ovaries
Spleen
Testes
Thymus
Thyroid (including parathyroid, weighed when fixed for at least 24 hours)
Uterus
Statistics:
Univariate one-way analysis of variance was used to assess the significance of intergroup differences. If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex. The Steel-test (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution. The Fisher-Exact test was applied to frequency data. All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of
significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.
Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
References: - C.W. Dunnett A Multiple Comparison Procedure for Comparing Several Treatments with a Control, J. Amer. Stat. Assoc. 50, 1096-1 121 (1 955).
- R.G. Miller Simultaneous Statistical Inference, Springer Verlag, New Yoh (1981).
- R.A. Fisher Statistical Methods for Research Workers, Oliver and.Boyd, Edinburgh (1950).
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):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
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: neoplastic:
effects observed, treatment-related
Details on results:
OBSERVATIONS
Group 1 (0 mg/kg bw/day) No mortality occurred.
Group 2 (20 mg/kg bw/day) One male (animal 17) was sacrificed for humane reasons on day 38 due to broken upper incisors and subsequent body weight loss. One female (animal 59) was found dead on day 19. Prior to death this animal showed calm behaviour, hunched posture, labored respiration, a pale appearance, piloerection and emaciation. Based on lung findings noted at microscopic examination this death was considered due to a gavage error.
Group 3 (100 mg/kg bw/day) One female (animal 70) died after blood sampling on day 94, just prior to necropsy. This was considered to be an accidental death.
Group 4 (500 mg/kg bw/day) Five males and eight females were found dead (day 5 and between days 33-57) or killed in (days 37, 57 and 58). The remaining animals were sacrificed on days 59 and 60.

CLINICAL SIGNS
Hunched posture was noted in two females of the 100 mg/kg dose group and in 2/10 males and 9/10 females of the 500 mg/kg dose group. Piloerection was observed in 6/10 males and 8/10 females receiving 500 mg/kg day. Males and/or females intercurrently sacrificed incidentally showed other clinical signs such as lethargy, labored respiration, pale appearance, diarrhoea, watery discharge from the eye, lethargy, ptosis, muscle twitching, uncoordinated movements, ventro-lateral recumbency, production of abnormal sounds, tremors and cold feeling.
Excessive salivation was seen in one female treated with 20 mg/kg/day and among all females and the majority of males of the 100 and 500 mg/kg dose groups. This is often noted in rats of this age and strain following oral gavage and considered to be related to multiple intraoesophageal intubation and/or an irritant or bad taste of the test substance. Therefore salivation was considered not to be a sign of systemic toxicity.
Hunched posture was observed in one female receiving 20 mg/kg/day on a few days in weeks 6 and 7 only. Based on the low incidence and the time of occurrence this finding was considered to have occurred by chance without a relationship with treatment. Other (incidental) findings noted in control and treated animals were considered to be within the range of biological variation for these animals treated by oral gavage. In the absence of a dose-response relationship or similar findings in the opposite sex these findings were considered to be toxicologically irrelevant.

FUNCTIONAL OBSERVATIONS
There were no findings noted during functional observations and the variation in motor activity did not indicate a relation with treatment.

BODY WEIGHT
Body weight and body weight gain of males and, to a lesser extent, of females receiving 500 mg/kg/day were decreased during treatment. Statistical significance was attained in most cases. Body weights and body weight gain of the other groups remained in the same range as controls
over the 13-week study period.

FOOD CONSUMPTION
Food consumption was slightly decreased in males and females receiving 500 mg/kg/day starting from respectively week 1 and week 8 until termination. No statistical significance was achieved. Relative food consumption (i.e. after correction for body weight) was slightly decreased in males
exposed to 500 mg/kg/day in week 1. Differences in relative food consumption between treated and control males on other days,.or between treated and control females were less apparent. There were no differences in food consumption before or after allowance for body weight between animals receiving 20 and 100 mg/kg/day and control animals.

OPHTHALMOSCOPIC EXAMINATION
Ophthalmoscopic examination did not reveal any abnormalities in control and treated animals.

CLINICAL LABORATORY INVESTIGATIONS
HAEMATOLOGY
Red blood cell count, haemoglobin and haematocrit values were decreased in females receiving 100 mg/kg/day. Prothrombin time was increased in males and females of this dose group. However, most of the values remained within the range of historical data found for rats of this age and strain. Other values in treated animals achieving a level of statistical significance when compared to coritrols mostly remained within the normal range of historical data for rats of this age and strain and/or were considered to have arisen as a result of slightly high or low control values.
Moreover, corroborative findings in the opposite sex were usually absent and these changes were therefore considered to be of no toxicological significance.

CLINICAL BIOCHEMISTRY
Chloride and total protein values were decreased in males and females dosed at 100 mg/kg/day. In addition, total cholesterol (females), globulin (females) and calcium (males) were decreased and urea (males), sodium (mates) and albumin/globulin ratio (females) were increased this dose group,
Other values in treated males and females achieving a level of statistical significance when compared to controls, were considered to be of no toxicofogical significance as a treatrnentrelated distribution and/or corroborative findings in the opposite sex were absent. Moreover, for certain parameters the values remained within the range of historical data found for rats of this age and strain.

PATHOLOGY
MACROSCOPIC EXAMINATION
Of the recorded macroscopic findings the following were considered to be related to treatment:
Stomach -thickened limiting ridge in 2 males and 3 females of Group 3 and in 3 males, and 5 females of Group 4.
Spleen - enlarged in 4 males and 2 females of Group 4.
Thymus - reduced in size in 4 males and 4 females of Group 4.
Other macroscopic observations at necropsy were considered to be within the range of biological variation for rats of this age and strain and not to represent a change of toxicological significance. Furthermore, these observations did not show a dose-response relationship

ORGAN WEIGHTS
Kidney:body weight ratios were increased in males receiving 100 mg/kg/day. Statistically significant changes in relative spleen weights and absolute thyroid weights of females dosed with 20 mg/kg/day were considered to be of no toxicoIogical significance as a treatment-related distribution and corroborative findings in the opposite sex were absent.

MICROSCOPIC EXAMINATION
The following microscopic findings were considered due to treatment with the test article: Stomach: minimal or slight squamous hyperplasia of the forestomach (correlates to necropsy observation) seen in five Group 4 and five Group 3 animals (males and females); Liver: minimal or slight hepatocellular hypertrophy in fifteen Group 4 (males and females) and three Group 3 males; Testes: slight seminiferous epithelial degeneration in two Group 4 males; Spleen: slight lymphoid hyperplasia in one Group 4 male and female, severe hemopoiesis (primarily erythropoiesis). in two Group 4 males (both correlates to necropsy observation); Thymus : moderate or severe atrophy {correlates to necropsy observation) in 6 males and 4 females of Group 4; Bone Marrow: slight to severe atrophy in 5 males and 6 females of Group 4, slight or moderate erythroid hyperplasia in 1 male and 2 females of Group 4. The bone marrow atrophy seen in group 4 rats was considered to have been a major contributory cause of mortality in this group. The remainder of microscopic findings recorded in animals which survived to terminal sacrifice were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated groups.
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified

ANALYSIS OF DOSE PREPARATIONS

Results are in a separate document under report nr. RGL F99113 T99005 A (doc is attached to 90 -day study, Notox study 260101). Analysis of the accuracy of formulations prepared on day 1 revealed values within the range of 79 (Group 2) to 302% (Group 4) of nominal. The slightly low sample values of Group 2 were considered acceptable for this study also because there was no indication of incorrect preparation of the formulations.

MORTALITY One female receiving 500 mg/kg/day was found dead on day 15. No further mortality occurred during the study period.

CLINICAL SIGNS No toxicologically significant changes in clinical signs were noted during the study. Excessive salivation was seen among animals of the 500 mg/kg dose group. This is often noted in rats of this age and strain following oral gavage and considered to be related to multiple intraoesophageal intubation and/or an irritant or bad taste of the test substance. Therefore salivation was considered not to be a sign of systemic toxicity. Other findings noted in control and treated animals were considered to be within the range of biological variation for these animals treated by oral gavage.

BODY WEIGHT Body weight gain of males receiving 500 mg/kg bw/day was slightly decreased at the end of the treatment period. Body weights and body weight gain of the other groups remained in the same range as controls over the 2-week study period.

FOOD CONSUMPTION Relative food consumption was slightly decreased among males and females receiving 500 mg/kg bw/day during the first week of treatment There were no differences in food consumption before or after allowance for body weight between other treated groups and control animals.

CLINICAL LABORATORY INVESTIGATIONS HAEMATOLOGY Red blood cell count, haemoglobin, mean corpuscular haemoglobin concentration (all in males) and total white blood cell count (males and females) were decreased in the 500 mg/kg dose group. In addition, prothrombin time, partial thrornboplastin time (males and females) and red cell distribution width (females) were increased in this dose group. Total white blood cell count was also decreased in females receiving 100 mg/kg bw/day, but since all values remained within the range of historical data for rats of this age and strain, the toxicological relevance of this finding is doubted. Haernatology parameters of other groups did not show any statistically signjfjcant changes when compared to controls.

CLINICAL BIOCHEMISTRY Total cholesterol, sodium and chloride values were decreased in males and females receiving 500 rnglkgfday. In addition, potassium, calcium (both in males) and total protein (females) were decreased and urea (males), total bilirubin and alkaline phosphatase values (both in females) were increased in this dose group. Other values in treated females achieving a level of statistical significance when compared to controls, were considered to have arisen as a result of slightly high'control values and in the absence of a treatment-related distribution or corroborative findings in the opposite sex, considered to be of no toxicological significance.

PATHOLOGY MACROSCOPIC EXAMINATION Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of systemic toxicity. Examination of the female receiving 500 mg/kg bw/day which was found dead revealed haemorrhage of the thymus. This observation and other incidental findings noted among treated and control animals were considered to be within the range of biological variation for rats of this age and strain in this type of study by oral gavage and not to represent a change of toxicological significance.

ORGAN WEIGHTS Liver:body weight ratios and thyroid:body weight ratios were increased and absolute testes weights were decreased in males receiving 500 mg/kg bw/day. No effects were seen on organ weights or organ:body weight ratios in animals dosed up to 100 mg/kg bw/day.

MICROSCOPIC EXAMINATION No histopathology was performed.

Conclusions:
From the results presented in this report a No Observed (Adverse) Effect Level (NO(A)EL) of 20 mg/kg/day was concluded. An effect on the thyroid gland, a known target organ of AMMONIUM THIOCYANATE, was not evident in this study; particularly total serum cholesterol and triglycerides are decreased in the 100 mg/kg dose group when compared to the control group (respectively -6.9% and -32% in males and -22.8%and -1 9% in females), while these parameters are usually increased in situations of hypothyroidism. This is consistent with the lack of pathotogical lesions and the unchanged weight of the thyroid gland in any of the dose groups, which are the most sensitive parameters for evaluating the thyroid function. Consequently, evaluations of levels of T3 and T4 have not been performed.
Executive summary:

90-Day oral toxicity study with AMMONIUM THIOCYANATE by daily gavage in the rat. Based on a 14-day range finding study, the dose levels for this 90-day oral gavage study were selected to be 0, 20, 100 and 500 mg/kg/day.

The study was based on the following guidelines.

- EEC Directive ,87/302/EEC, B Repeated Dose (90 days) Toxicity (oral), 1988.

- OECD 408, Repeated Dose 90-day Oral Toxicity Study in Rodents, 1998.

- EPA 71 2-C-96-199, 90-Day Oral Toxicity, 1996.

The test substance was administered daily for 92 or 93 days by oral gavage to SPF-bred Wistar rats. One control group and three treated groups were tested, each consisting of 10 males and 10 females.

The following parameters were evaluated: clinical signs daily; functional observation tests; body weight and food consumption weekly; ophthalmoscopy at pretest and in week 13. At scheduled termination: clinical pathology and organ weights. At interim and scheduled terminations: macroscopy, Histopathology was performed on a selection of tissues.

RESULTS .

Formulation analysis revealed values within the range of 74-102% of nominal (reported separately by the sponsor).

20 mg/kg/day

- No treatment-related findings. Two accidental deaths occurred.

100 mg/kg/day

- One accidental death occurred after blood sampling. - Hunched posture (2/10 females).

- Decreased, red blood cell count, haemoglobin and haematocrit (females) and increased prothrombin time (males/females).

- Decreased chloride, total protein (females/males), total cholesterol (females), globulin (females) and calcium (males); increased urea (males), sodium (males) and albumin/globulin ratio (males).

- Macroscopic examination revealed a thickened limiting ridge of the stomach (males/females)

- Increased kidney:body weight ratio (males)

- Microscopic examination revealed minimal or slight squamous hyperplasia of the forestomach (males/females)) and minimal hepatoceflular hypertrophy (males).

500 mg/kg/day

- Five males and eight females were found dead or killed in extremis. The remaining animals were sacrificed.

- Hunched posture and piloerection (males/females) and incidelitally lethargy, labored respiration, pale appearance, diarrhoea, watery discharge from the eye, lethargy, ptosis, muscle twitching, uncoordinated movements, ventro-lateral recumbency, production of abnormal sounds, tremors and cold feeling.

- Due to premature mortality, clinical signs and severe reduction of body weights, dosing of Group 4 animals was stopped from day 59 onwards and the remaining animals were sacrificed on day 59 or 60. Consequently no clinical pathology data and organ weights were available for this group.

- Reduction of body weight and body weight gain (males/females).

- Slight reduction of food consumption starting from week 1 (males) or 8 (females).

- Macroscopic examination revealed a thickened limiting ridge of the stomach, an enlarged spleen and a reduced size of the thymus (males/females).

- Microscopic examination revealed findings in the forestomach (minimal or slight squamous hyperplasia, males/females), liver (minimal or slight hepatocellular hypertrophy, males/females), testes (slight seminiferous epithelial degeneration, males), spleen (slight lymphoid hyperplasia, males/females and severe hemopoiesis, primarily erythropoiesis, males), thymus (moderate or severe atrophy, males/females), bone marrow (slight to severe atrophy and slight or moderate erythroid hyperplasia, males/females).

CONCLUSION

From the results presented in this report a No Observed (Adverse) Effect Level (NO(A)EL) of 20 mg/kg/day was concluded. An effect on the thyroid gland, a known target organ of AMMONIUM THIOCYANATE, was not evident in this study; particularly total serum cholesterol and triglycerides are decreased in the 100 mg/kg dose group when compared to the control group (respectively -6.9% and -32% in males and -22.8%and -1 9% in females), while these parameters are usually increased in situations of hypothyroidism. This is consistent with the lack of pathotogical lesions and the unchanged weight of the thyroid gland in any of the dose groups, which are the most sensitive parameters for evaluating the thyroid function. Consequently, evaluations of levels of T3 and T4 have not been performed.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The selected study is GLP compliant and has Klimisch score 1.

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

Mode of Action Analysis / Human Relevance Framework

Additional information

There is one acceptable study report available in rats that was performed with ammonium thiocyanate according to OECD408 and GLP.

In this 90-day study in rats mortality was observed after daily exposure to ammonium thiocyanate at a level of 500 mg/kg bw per day.

At 500 and 100 mg/kg bw signs of toxicity include changes in haematological and clinical chemistry parameters. Based on these effects, the NOAEL for 90 day exposure is 20 mg NH4SCN/kg bw/day. In this study the thyroid has not been examined functionally (no detection of parameters TSH, T4 and/or T3 levels in blood).

 

Anderson & Chen (1940) performed a study with potassium and sodium thiocyanate with dogs in which the dog seemed to be a more sensitive species. A dose level of 100 mg/kg bw per day (sodium or potassium salt) caused a progressive loss of weight, apathy, head droop, ataxia, and ultimate death. In the animals that died, the blood concentration of thiocyanate exceeded 20 mg per 100 cc. blood. Dogs receiving about 20 mg NaSCN or KSCN/kg bw per day for 12 weeks were in excellent condition throughout, and blood thiocyanate levels were below 12 mg SCN-/100 mL.

 

Lesions in thyroid glands consisting of an increased number of vacuoles in the colloid of goats treated with potassium thiocyanate are observed after 30 days treatment with 4.5 mg/kg bw/day via oral gavage (Soto-Blanco et al., 2008).

 

In an other study potassium thiocyanate (1000 mg/kg diet ± 1 -2 kg consumption per day = 1000 -2000 mg/kg KSCN per day) was fed to pigs in their diet with our without iodine supplement for 119 days. Hypothyroidism was provoked only when there was no supplemental iodine (Schöne et al., 1997).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Appropriate study of the highest quality and validity

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Exposure via inhalation is not expected. The vapour pressure is very low (0.015 Pa, and probably much lower. See vapour pressure) and thus does not present any potential for inhalation exposure due to volatilization of the salt. Furthermore thiocyanates are very hygroscopic (see granulometry). Inhalable particles are not available and will also not be formed during handling and use of the substance.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Low likelihood of exposures.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Dermal absorption is lower than absorption via oral route, whereas for systemic toxicity the route of absorption itself makes no difference.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
No studies performed. Ammonium thiocyanate is not irritating to the skin and not sensitising. Most important effects are therefore systemic rather than local.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other

Justification for classification or non-classification

The overall lowest sub-chronic NOAEL is 20 mg ammonium thiocyanate/kg bw/day, based on effects on clinical chemistry, haematology and histopathology of liver, bone marrow and thymus at 100 and 500 mg/kg. These types of effects and this dose level do not warrant classification for STOT-RE.