COAGULANT 122 (SOLID)

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26.01.1995 - 13.04.1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

92/69/EEC

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

28-day or 14-day study

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Details on test material:

Name of test material (as cited in study report): Coagulant 122 (solid)
Substance type: Clear slightly viscous yellow liquid
Physical state: 80.2% solids
Batch number: 9435262-8489-A
Storage condition of test material: 4°C in the dark under an inerte atmosphere

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

The rats were 28+/-1 days old, in a weight range of 69-88 g on arrival. A 15 day acclimatisation period was allowed between delivery of the animals and start of treatment.

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

water

Remarks:

Distilled water

Details on oral exposure:

Method of administration:
Gavage

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
concentrations of 1 mg/ml and 100 mg/ml.
Basis:
nominal in water

No. of animals per sex per dose:

Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

There were no mortalities and n clinical signs observed during the study that were considered to be of toxicological importance.

Mortality:

no mortality observed

Description (incidence):

There were no mortalities and n clinical signs observed during the study that were considered to be of toxicological importance.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no statistically significant differences from control recorded for bodyweight gain for any of the treatment groups.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

food consumption over the treatment period was comparable for control and treated groups.

Haematological findings:

no effects observed

Description (incidence and severity):

There were no differences from ontrol for haemtological parameters measured that were considered to be related to treatment.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There were no statistically significant differences from control in the biochemical parameters measured.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Liver and kidney weights (bodyweight adjusted) and spleen and adrenal weights (absolute) were statistically significantly higher for male rats treated at 1000 mg/kg/day than for controls.

Gross pathological findings:

no effects observed

Description (incidence and severity):

The macroscopic exmination performed at termination revealed no changes attributable to treatment with Coagulant 122 (solid).

Details on results:

Clinical observations:
No moralities occured during the study. There were no
clinical signs observed during the study considered to be of
toxicological importance.

Laboratory findings:
There were no differences from control for haematological
or biochemical parameters measured that were considered to
be related to exposure.

Effects in organs:
There were no macroscopic or microscopic changes observed
that were considered to be attributable to treatment.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

2

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

FORMULATION ANALYSIS

The analitical results confirm that the formulations analysed during the study were accurately formulated. The results also confirm that specimen formulations were stable during storage at ambient temperature for up to 4 hours, a period representing the maximum time from preparation to completion of dosing.

CLINICAL SIGNS (Appendix 5)

There were no mortalities.

There were no clinical signs observed during the study that were considered to be of toxicological imponance.

Increased salivation after dosing was noted on isolated occasions in male rats receiving 1000 or 150 mg/kg/day during the study. An increase in salivation following dosing in commonly observed in orally dosed rat studies and is considered to be a result of the unpalatability of the test substance and therefore not of toxicological importance.

BODYWEIGHT (Figure2,Table 1, Appendix 1)

There were no statistically significant differences from control recorded for bodyweight gain for any of the treatment groups. Considerable variation in bodyweight gain was noted for female rats (up to 22% highet than control for females treated at 150 mg/kg/day). There was no dosage relationship and a treatment-related effect on bodyweight gain was not suspected.

FOOD CONSUMPTION (Figure 3, Table 2)

Food consumption over the treatment period was comparable for control and treated groups.

HAEMATOLOGY (Table 3, Appendix 2)

There were no differences from control for haematological parameters measured that were considered to be related to treatment.

Statistically significantly lower than control packed cell volume (PCV) and haemoglobin concenrration (Hb) were recorded for all treated male rats. Haemoglobin concentration was also lower than control for females at 1000 mg/kg/day and the blood red cell count lower for males at 1000 mg/kg/day. The magnitude of these differences from control was small and the majority of individual values were within the expected range for rats of this age and srrain. Additionally, the control values for pCV and Hb for some control males were higher than expected. These differences from control were not considered to be related to treatment at this stage.

BIOCHEMISTRY (Table 4, Appendix 3)

There were no statistically significant differences from control in the biochemical parameters measured.

ORGAN WEIGHTS (Table 5, Appendix 4)

Liver and kidney weights (bodyweight adjusted) and spleen and adrenal weights (absolute) were statistically significantly higher for male rats treated at 1000 mglkglday than for controls. The macroscopic appearance of these tissues was normal and there were no associated histopathological changes. Therefore a treatment-related effect on these tissues was not suspected.

There were no other differences from control in the organ weights measured.

MACROSCOPIC PATHOLOGY (Table 6, Appendix 5)

The macroscopic examination performed at termination revealed no changes attributable to treatment with Coagulant 122 (solid).

MICROSCOPIC PATHOLOGY (Table 7, Appendix 5)

No treatment-related changes were seen in any of the organs that were examined. The changes that were seen were within the normally expected range of spontaneous changes commonly encountered in animals of this species and age range.

No changes were seen that might account for the weight increases reported at necropsy in male liver, spleen, kidneys and adrenals.

Applicant's summary and conclusion

Conclusions:

Coagulant 122(solid),a'watertreatment,was administered to groups of rats at dosages of 1000, 150 or 15 mg/kg/day for 29 consecutive days. A group of control rats received the vehicle, distilled water, alone.
There were no differences from control in any of the parameters investigated that were considered attributable to treatment with Coagulant 122 (solid).
It was considered that 1000 mg/kg/day represents a no observed effect level (NOEL) for Coagulant 122 (solid) when administered for at least twenty-eight consecutive days to the rat. According to EEC Council Directive 79/831/EEC Annex VI, Part II(D) as described in Commission Directive 93/21/EEC,labelling with the R48 risk phrase is not required for Coagulant 122 (solid).

Executive summary:

This study was performed to assess the systemic toxicity of Coagulant 122 (solid) to the rat. The method followed was that outlined in Annex V, Part B, Method 87 in the EEC Directive92/69/EEC and OECD Guideline for Testing of Chemicals No. 407 'Repeated Dose Oral Toxicity - Rodent: 28-day or 14-day study'.

Coagulant 122 (solid) was administered by oral gavage once daily to groups of five male and five female rats for twenty-nine days at dosage levels of 15, 150 and 1000 mg/kg/day. The test substance was prepared as solutions in distilled water at concentrations of 1.87, 18.7 and 124 mg/ml, based on a solids content of 80.2%, and was administered at a dosage volume of l0 rml/kg/day.

A further group of rats (5 males and 5 females) was held as a control receiving the vehicle alone at the same dose volume (10 ml/kg/day).

Bodyweights, food and water consumption and clinical observations were recorded during the study. Blood samples for clinical investigations were taken on Day 27 and all animals were killed and examined macroscopically on Day 30. Histopathological examination of specified tissues was then initiated.

There were no differences from control in parameters measured, namely mortality, clinical signs, bodyweight, food consumption, water consumption, haematology, biochemistry, macroscopic and microscopic pathology that were considered to be related to treatment.

Conclusion

It was considered that 1000 mg/kgiday represents a no observed effect level (NOEL) for Coagulant 122 (solid) when administered for at least twenty-eight consecutive days to the rat. According to CLP Regulation (EC) 1272/2008, labelling with H373 hazardous phrase is not required for Coagulant 122 (solid).