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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 Aug 2004 to 23 Nov 2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented study, similar to guidelines, but with certain deviations; quality assured data which meets basic scientific principles

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2005
Reference Type:
secondary source
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
No haemotology, opthalmology or behavioural tests, and only a limited number of organs examined microscopically
GLP compliance:
no
Remarks:
“This Report has been audited by Quality Assurance and found to reflect the data generated for this study.”
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Cereclor S52
- Substance type: technical product
- Physical state: pale yellow liquid
- Analytical purity: no data
- Impurities (identity and concentrations): no stabiliser
- Composition of test material, percentage of components: C14-17 chlorinated paraffin; 52% chlorinated
- Storage condition of test material: approx. -20oC

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Harlan UK Ltd., Shaw’s Farm, Bicester, Oxfordshire, UK- Age at study initiation: 5-8 weeks on arrival- Housing: 2/cage on sawdust in solid-bottomed, polypropylene cages- Diet: ad libitum (powdered RM1 diet supplied by Special Diet ServicesLtd., Stepfield, Witham, Essex, UK)- Water: ad libitum- Acclimation period: >=5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 19-23- Humidity (%): 40-70- Air changes (per hr): nominal 14-15- Photoperiod (hrs dark / hrs light): 12/12IN-LIFE DATES: From: 23-Aug-2004 To: 23-Nov-2004

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION- Rate of preparation of diet (frequency): monthly- Mixing appropriate amounts with (Type of food): RM1 diet- Storage temperature of food: approx. -20oCVEHICLE- Justification for use and choice of vehicle (if other than water): - Concentration in vehicle: - Amount of vehicle (if gavage): - Lot/batch no. (if required): - Purity:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
“Analyses of the diet formulations were undertaken with regard to concentration, homogeneity and stability. Dose groups prepared at concentrations of 0 ppm, 300 ppm and 3000 ppm were analysed by Inveresk Research... Dose groups prepared at concentrations of 0 ppm, 30 ppm and 100 ppm were analysed by CXR Biosciences...”
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
continuous
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:0, 30, 100, 300 and 3000 ppmBasis:nominal in diet
Remarks:
Doses / Concentrations:0, 2.4, 9.3, 23, 222 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
10/sex in each treatment group, 20/sex in control group
Control animals:
yes, plain diet
Details on study design:
- Rationale for animal assignment (if not random): ”Group allocations were made in such a manner that the mean body weight in each group was similar.”
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes- Time schedule: dailyDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: study termiinationBODY WEIGHT: Yes - Time schedule for examinations: weeklyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: YesFOOD 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 OPHTHALMOSCOPIC EXAMINATION: No HAEMATOLOGY: No CLINICAL CHEMISTRY: Yes - Time schedule for collection of blood: at termination- Animals fasted: No data- How many animals: all- Parameters checked in table [No.?] were examined. serum samples - sodium, chloride;plasma samples - potassium, blood urea nitrogen (BUN), creatinine, total protein, albumin, globulin, ALT, AST, ALP, gamma-GT, bilirubin, triglycerides, cholesterol and glucoseURINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: NoOTHER: hepatic T4-UDPGA glucuronyl transferase activity, hepatic peroxisome proliferation, free and total plasma T4, T3 and TSH levels and renal and hepatic alpha2u globulin levels
Sacrifice and pathology:
Organ weights - liver and kidneyHistopathology - liver, kidney and thyroid
Other examinations:
no data
Statistics:
“Statistical comparisons between treated and control groups have been undertaken for all numerical data sets".

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY No treatment-related deaths or clinical signs BODY WEIGHT AND WEIGHT GAIN No adverse effects on terminal bodyweight or body weight gainFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) No effects on food consumption. See Remarks on results ... for compound intake dataCLINICAL CHEMISTRYSmall but statistically significant decreases in plasma triglycerides (by 28-39%) and cholesterol (by 14-23%) were observed in the top dose animals onlyORGAN WEIGHTSIn the 3000 ppm animals, absolute and relative liver and kidney weights were significantly increased by 13-35% and 9-16% of the control values respectively. No effects on liver or kidney weights were observed at the lower dose levelsHISTOPATHOLOGY: NON-NEOPLASTICMinimal centrilobular hepatocyte hypertrophy was noted in the liver of 9/10 top dose males. No treatment-related histopathology was observed in the kidney or thyroid of the treated animalsOTHER FINDINGSIn males, small but statistically significant decreases in plasma free T3 levels were seen at the two highest dose levels (by 26 and 22% respectively). However, there were no effects on total T3 levels or on free and total T4 levels.There was also a slight increase in plasma TSH levels (by 17%) but at the top dose only. In females, there were no effects on plasma free or total T3 levels, or on plasma total T4 levels, but a statistically significant increase (by 41%) in plasma free T4 levels at the top dose. A dose-related increase in plasma TSH levels was observed at the two highest dose levels (by 20 and 39% respectively).Hepatic microsomal T4-UDPGA glucuronyl transferase activity was increased in the top dose males (by 82%) and in the 100, 300 and 3000 ppm females (by 30, 30 and 254% respectively). There was no effect of MCCPs administration on hepatic peroxisome proliferation as determined by palmitoyl CoA oxidation. Alpha2u globulin levels (determined by Western blotting) from kidney or liver homogenates were also unaffected by treatment in males. As expected, alpha2u globulin was not detected in female kidney or liver homogenates.

Effect levels

Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Significant effects on organ weights, clinical chemistry and liver histopathology at top dose only; C14-17 chlorinated paraffin (52% chlorinated)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Dietary concentration

(ppm)

Compound intake

(mg/kg bw/day)

Male

Female

0

0

0

30

2.38

2.51

100

9.34

9.70

300

23.0

24.6

3000

222

242

The biological significance of the increase (rather than a decrease) in plasma free T4 levels in females at the top dose is unclear and it is considered likely to be a chance finding

Applicant's summary and conclusion

Conclusions:
Overall, there were no adverse effects seen in this 90-day study in rats at exposure levels up to 300 ppm of Cereclor S52 (about 23.0 and 24.6 mg/kg bw/day in males and females, respectively), suggesting a NOAEL of 300 ppm for both male and female rats.
Executive summary:

Cereclor S52 (a C14 -17 chlorinated paraffin; 52% chlorinated) was administered in the diet to male and female Fischer 344 rats (10/sex/dose) for 90 days at concentrations of 30, 100, 300 and 3000 ppm. The resultant ingested dose levels were about 2.38, 9.34, 23.0 and 222.5 mg/kg bw/day for male rats and 2.51, 9.70, 24.6 and 242.8 mg/kg bw/day for female rats.

 

There were no treatment-related effects on terminal body weight, body weight gain or food consumption. Absolute and relative liver and kidney weights were increased only at the 3000 ppm dose level in male and female rats.

 

The only toxicologically significant effects seen in the clinical chemistry data were small but statistically significant decreases in plasma triglycerides (by 28-39%) and cholesterol (by 14-23%) in the top dose animals only. Small, inconsistent changes in thyroid hormones were deemed not to be adverse, particularly since no concurrent histopathology was observed.

Minimal centrilobular hepatocyte hypertrophy was noted in the liver of male rats receiving 3000 ppm. This was not evident in male rats at the lower dose levels or in female rats at any dose. No treatment-related histopathology was reported in the kidneys or thyroid of male or female rats administered Cereclor S52 at dose levels of up to 3000 ppm.

 

Based on these data a NOAEL of 300 ppm is suggested, which equated to 23.0 and 24.6 mg/kg bw/day for male and female rats respectively.