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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Significant shortcomings compared to protocol requirements, both in terms of reporting (eg little animal husbandry information) and procedures (eg only two dose groups, only 4hrs exposure/day). However, the study does address the known critical end points for this substance and does establish a NOAEL usable for risk assessment purposes for this dose route.

Data source

Reference
Reference Type:
publication
Title:
Percutaneous toxicity of ethylene glycol monomethyl ether and of dipropylene glycol monomethyl ether in the rat
Author:
Fairhurst S, Knight R, Marrs, TC et al
Year:
1989
Bibliographic source:
Toxicology, 57, 209-15

Materials and methods

GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Analytical purity: 99%
- Supplied by Aldrich Chemical Co.

Test animals

Species:
rat
Strain:
other: Porton Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: in range 170-240g.

Administration / exposure

Type of coverage:
other: occluded and open
Details on exposure:
TEST SITE
- prepared by removing fur from dorsal skin using electric clippers.
- Type of wrap if used: For occluded animals, patch was covered with aluminium foil held in place by ‘Blenderm’ tape and left covered for 4 hours.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
Doses applied daily, 5 days/week.
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 1000mg/kg
Basis:

No. of animals per sex per dose:
8
Control animals:
other: exposed to water at 1000mg/kg.

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: Daily

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, daily

HAEMATOLOGY: Yes
- Blood samples (lithium heparin) were taken at the start from the caudal vein, and after 14 and 28 days exposure. After centrifugation, the plasma was assayed for total protein, creatinine, glucose, blood urea nitrogen, 5’nucleotidase, creatine kinase, apartate aminotransferase and alkaline phosphatase (ALP) using an Abbot analyzer and ‘A-gen’ reagents. Haematology was carried out on dipotassium EDTA samples from the caudal vein.
Sacrifice and pathology:
After 28 days, all animals were sacrificed using sodium pentabarbitone and the testes weighed. Samples of liver, kidney, skin (application site) stomach, small and large intestines were processed for histology (H&E staining) along with the testes. Lung samples were included where there was visual evidence of abnormality. Bone marrow smears were prepared from the left femur of each rat and stained using May-Grunwald and Giesma stains. The other femur from each animal was decalcified and processed for H&E staining.
Statistics:
Unpaired Student t test for continuous variables, Fischer’s test for histology data.

Results and discussion

Results of examinations

Clinical signs:
not specified
Dermal irritation:
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
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:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN
Weight gain and food intake was reduced at 1000mg/kg (both occluded and non-occluded animals) and at 100mg/kg (occluded animals.) A similar pattern was seen with food intake.

HAEMATOLOGY
Over the 28 days, in the high dose occluded group significant reductions were seen in white blood cells, haemoglobin, PCV and MCV but increased number of reticulocytes.

CLINICAL CHEMISTRY
No differences were seen in clinical chemistry parameters except for ALP in the occluded group (assumed to be high dose group) where a marked reduction was seen with exposure.

ORGAN WEIGHTS
Testes weight reduction was evident for both high dose group animals.

HISTOPATHOLOGY:
Histological changes attributed to treatment were only observed in the testes and bone marrow and only in the high dose occluded group. Testes observations included depletion of pachytene spermatocytes and almost complete absence of spermatids and spermatozoa. The germinal epithelium appeared reduced in size but Sertoli and Leydig cells appeared normal and spermatogonia appeared unaffected. The bone marrow sections showed generalized hypocellularity. The bone marrow smears showed no deviation from control groups in any dose group.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 100 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: body weight gain, food intake under occluded conditions
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: all other effects under both occluded and non occluded conditions
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: body weight gain, testes (non-occluded conditions)
Dose descriptor:
LOAEL
Remarks:
critical effects
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: body weight gain, testes, haematology, clinical chemistry, bone marrow (occluded conditions)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

A study examined the sub-acute percutaneous toxicity of methoxyethanol in rats. Animals were subjected to daily doses of 100 or 1000mg/kg under both occluded and non-occluded conditions for a period of 28 days. The only effect seen at the lower dose was reduced body weight gain and food intake under occluded conditions. At the higher dose, significant toxicity was observed with adverse effects body weight reduction, on the testes, haematology and clinical chemistry (limited to reduced ALP levels), and the bone marrow. Only the first two were seen under non-occluded conditions.

Synopsis

NOAEL (28 days, rats): <100mg/kg (occluded conditions, body weight only adverse effect)

NOAEL (28 days, rats): 100mg/kg (non-occluded conditions)