Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was not conducted to recognised guidelines, nor to GLP. The study report was unclear in places.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Test guideline
Qualifier:
no guideline followed
Deviations:
yes
Remarks:
only two treatment doeses were included (guidleine reccomends 3) Elizerabethan collars were used to prevent ingestion. The test site was not covered with a gauze patch
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
The test item belongs to the same chemical group as the submission substance (aryl/alkyl sulfonates).

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: HARE Rabbits for Research
- Weight at study initiation: males, 1.6-2.8kg; females, 1.6-2.5kg
- Housing: Individually in stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 10-24°C
- Humidity (%): 17-65%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Administration / exposure

Type of coverage:
open
Vehicle:
other: mineral oil
Details on exposure:
TEST SITE
- Area of exposure: 6.5 x 5 cm
- Surface area: 25%
- Time intervals for shavings or clipplings: Monday and Thursday of each week


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wiping with paper towels
- Time after start of exposure: 6 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 ml/kg

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hours
Frequency of treatment:
5 times per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25, 100 %
Basis:
other: w/v in primol 205
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Daily


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No


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: No
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Termination
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: Termination 10/sex/group


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals:Termination: 10/sex/group


URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.


NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
ANOVA with Dunnett's test
Regression analysis
Kruskal-Walis and Dunn's summed rank test
Joncheere's test for monotonic trend

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
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
There were a number of mortalities in the study, One control and four high dose animals died or were sacrificed early in the study. One control female was sacrificed during the recovery phase. Two high dose males were sacrificed moribund during the treatment period. one high dose male was found dead during recovery. One high dose female was sacrificed during recovery. Cause of death was not established.

Alopecia was observed throughout the study in treated animals. In addition there were numerous incidences of erythema, oedema, atonia, desquamation, fissuring and exfoliation in treated animals but without dose response. These findings decreased in recovery phase.

BODY WEIGHT AND WEIGHT GAIN
Mean body weights were slightly reduced in treated groups but evaluation is confounded by the small number of animals.

FOOD CONSUMPTION
Not recorded

FOOD EFFICIENCY
Not recorded

WATER CONSUMPTION
Not recorded

OPHTHALMOSCOPIC EXAMINATION
Not recorded

HAEMATOLOGY
The mean total leukocyte count of low and high dose females was lower at termination of treatment. Mean haemaglobin and haemocrit values and mean erythrocyte counts were also reduced.

CLINICAL CHEMISTRY
Decreases in total protein and globulin levels occurred.

URINALYSIS
Not recorded

NEUROBEHAVIOUR
Not recorded

ORGAN WEIGHTS
Absolute and relative weights of testes and epididymis were decreased in low and high dose males, together with increases in mean and absolute liver weights.

GROSS PATHOLOGY
Discolouration of the liver was observed in males and females. Testes were small.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic examination revealed treatment related morphological changes in the skin, testes, epididymis and possibly liver.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not recorded

HISTORICAL CONTROL DATA (if applicable)
Not recorded

Effect levels

open allclose all
Dose descriptor:
NOAEL
Basis for effect level:
other: Effects were observed at the lowest dose tested, therefore a NOAEL cannot be identified from this study.
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
LOAEL
Effect level:
< 250 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Effects observed at the lowest dose, therefore an arbitary LOAEL has been identified.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Incidence of selected pathologies

 

Parameter

n=10/sex

Dose level

Control

25

100

Recovery control

Recovery 25

Recovery 100

Small testis

M

 0/10

 3/10

 6/13

 0/5

 0/5

 1/3

 

Table 2: Absolute and relative organ weights

 

 

Males

Females

DAILY DOSE
(units e.g. mg/kg bw/day)

0

25

100

0

25

100

 

NUMBER OF ANIMALS

 10

 10

 10

 10

 10

 10

 

BODY WEIGHT (g)a

 -

 -

 -

 -

 -

 -

 

LIVER

 

 

 

 

 

 

 

Absolute Weighta

g

 70.850

74.006 

92.314 

 73.677

82.772 

90.501 

 

Per Body Weighta

%

 2.93

3.11 

3.83 

 2.72

 3.05

3.95 

 

TESTES

 

 

 

n.a.b

n.a.b

n.a.b

 

Absolute Weighta

g

 3.047

2.421 

1.997 

n.a.b

n.a.b

n.a.b

 

Per Body Weighta

%

 12.49

10.16 

7.76 

n.a.b

n.a.b

n.a.b

 

 

aGroup means at the end of terminal necropsy are shown.

bn.a. = not applicable

* p<0.05, ** p<0.01

Applicant's summary and conclusion

Conclusions:
Toxicity occurred at all doses tested, therefore a NOAEL has not been identified. an arbitary LOAEL of 250 mg/kg bw has been identified, based on effects at the lowest dose.
Executive summary:

In a  repeat-dose dermal toxicity study,  an alkaryl magnesium salt derivative was applied to the shaved skin of 15white rabbits/sex/dose at dose levels of 0, 25 and 100%, 6 hours/day for 5 days/week during a 28-day period.

 

A NOAEL cannot be identified from this study, as effects were observed at the lowest dose.

 

This dermal toxicity study in the rabbit is acceptable.