Isopentyl acetate

Repeated dose toxicity: other routes

Administrative data

Endpoint:

repeated dose toxicity: other route

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: not performed according to official test guideline but general scientific principles; not GLP and with limitations in study design and statistical analysis of results

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Experimental study for the carcinogeniceffect 3 representatives of solvents: propanol-1, 2-methyl) propanol-1 and 3-methylbutanol-1 (DE)

Author:

Gibel W, Lohs KH, Wildner GP and Schramm T

Year:

1975

Bibliographic source:

Geschwulstforsch. 45/1: 19-24

Reference 2

Reference Type:

publication

Title:

Experimental study for the carcinogeniceffect 3 high order alcohols: 3-methyl-1-butanol, propanol-1 and 2-methyl-1-propanol (DE)

Author:

Gibel W, Lohs KH, Wildner GP and Schramm T

Year:

1974

Bibliographic source:

Z Exper Chirurg 7: 235-239

Reference 3

Reference Type:

publication

Title:

Experimental study on carcinogenic activity of propanol-1, 2-methylpropanol-1 and 3-methylbutanol-1.

Author:

Gibel et al.

Year:

1974

Bibliographic source:

Gibel W, Lohs KH, Wildner GP (1974), Arch Geschwulstforsch 45: 19–24

Reference 4

Reference Type:

review article or handbook

Title:

"4.7 Carcinogenicity" in "Pentyl acetate (all isomers)" - referring to Gibel et al. (1974), Barilyak and Kozachuk (1988) and others

Author:

MAK

Year:

1996

Bibliographic source:

The MAK Collection for Occupational Health and Safety, Vol. 11, pp. 211-223 (p. 219-220), completed 28.03.1996, online posting date Sep 17 2004, available from Wiley InterScience

Materials and methods

Principles of method if other than guideline:

study of carcinogenic effects; histological examination of all organs, histological examination of vertebral bodies and femur, blood smear and differential blood count, leucocyte count

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

isoamyl alcohol

IUPAC Name:

isoamyl alcohol

Details on test material:

- Name of test material (as cited in study report): 3-methyl-1-butanol - Test substance No. 88/56
- Lab. J. No.: H 21670
- Physical state: liquid/colourless
- Analytical purity: >98%
- Stability under test conditions: The stability was ensured for the study period under the specified st orage conditions by reanalysis ( see report of Nov 25 1988)
- Storage condition of test material: at room temperature
Abbreviations for substances: "MEB" for 3-Methyl-1-butanol "MEP" for 2-Methyl-1-propanol

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Information provided in Gibel et al. (1974):
Wistar Ratten einer Koloniezucht, beidgeschlechtlich, bei Versuchsbeginn 10 Wochen alt
Tiere mit Preßlingen einer Standardkost ernährt, Wasser ad libitum
Kontrolltiere erhielten physiologische NaCl-Lösung, abgetötet am 643. Tag
(original German information)

Wistar rats of a colony breed, of both sexes, at beginning of study 10 weeks old
Animals fed with pellets of a standard diet, water ad libitum
Control animals received physiological NaCl-solution, were killed on day 643
(translated into English)
---
Information provided in Gibel et al. (1975):
Wistar Ratten einer konventionell gehaltenen Koloniezucht, beidgeschlechtlich, bei Versuchsbeginn ca. 10 Wochen alt
Tiere mit Preßlingen einer Standardkost ernährt, Wasser ad libitum
Kontrolltiere erhielten physiologische NaCl-Lösung (0.9 % NaCl) subkutan
(original German information)

Wistar rats of a conventionally kept colony breed, of both sexes, at beginning of study ca. 10 weeks old
Animals fed with pellets of a standard diet, water ad libitum
Control animals received physiological NaCl-solution (0.9 % NaCl) via subcutaneous application
(translated into English)

Administration / exposure

Route of administration:

subcutaneous

Duration of treatment / exposure:

until spontaneus death or the longest 643 days (when control animals were killed)

No. of animals per sex per dose:

Gibel et al. (1974):
30 animals in control group (no information about number of female/male animals)
24 animals in test group (no information about number of female/male animals)

Gibel et al. (1975):
25 animals in control group (no information about number of female/male animals)
24 animals in test group (no information about number of female/male animals)

Control animals:

other: yes, concurrent, treated with physiological NaCl solution

Examinations

Observations and examinations performed and frequency:

Information provided in Gibel et al. (1974/1975):
Alle Tiere bis zum Spontantod beobachtet, seziert und histologisch aufgearbeitet.
Untersuchungen:
Histologische Untersuchungen aller Organe
Histologische Untersuchungen von Wirbelkörpern und Femur
Blutausstrich und Leukozyten-Differentialblutbild
Leukozytenzählungen
(original German information)
All animals were observed until spontaneous death, dissected/anatomised and histologically processed.
Examinations:
Histological examinations of all organs
Histological examinations of vertebral bodies and femur
Blood smear and differential blood count
Leucocyte count
(translated into English)
---
Additional information provided in Gibel et al. (1975):
Ratten in regelmäßigen Abständen gewogen, bei Mehrzahl der Tiere erfolgte eine Verlaufskontrolle des Blutbildes. Normalwerte der Kontrolltiere des gleichen Stammes wurden genommen.
(original German information)
Rats weighed at regular time intervals, for the majority of the animals the blood count was monitored. Standard values of the control animals from the same clade were taken.
(translated into English)

Results and discussion

Results of examinations

Details on results:

Mortality:
Mean lifetime of treated animals was decreased: 592 d (treatment group) versus 643 d (control group)
---
Tumour development:
Benign tumours:
2 in control group with 25 animals
5 in treatment group with 24 animals
Malign tumours:
0 in control group with 25 animals
10 in treatment group with 24 animals
10 malign tumours/cancer development in the treatment group included: 4 liver sarcoma, 2 liver carcinoma, 1 spleen sarcoma, 1 glandular stomach carcinoma, 2 myeloid leukemia.

---

Other effects of toxicity (it was not specified which of the three test substances - also 2-Methylpropanol-1 and Propanol-1 were tested besides 3-Methyl-1-butanol - specifically caused these effects. Gibel et al. speak of the substances as a group):
Pathological findings included toxic liver damage (steatosis, congestion, single cell and grouped cell necrosis, fibrosis, cirrhosis)
In some animals changes in the myokard with scar formation was observed, rarely also with slight perivascular inflammtory infiltrate.
In single cases, interstitial pancreatitis and fibrosis was found at the pancreas.
---
In the discussion part, Gibel et al. (1975) explain that there was (independent of the tested substance) a carcinogenic effect but also a strong liver toxic effect in almost all animals as well as hyperplasia of
the haematopoietic parenchyma. They say it needs to be concluded that there was a carcinogenic effect but also hepatotoxic and haematotoxic effects.

Effect levels

Dose descriptor:

other: LOAEL (disregarded)

Effect level:

4.6 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Although there are limitations in the quality of the study (when compared to the standard of today's official test guideline studies), the test substance plus its purity was identified sufficiently, it was administered over a long period (1.75 years) and the incidence of toxic effects from treatment versus no treatment was apparent even at the test group size of 24. Furthermore, toxic effects were also found by Gibel et al. (1974/1975) in a second independent experiment upon oral administration (see 7.5.1 Repeated dose toxicity: oral).

A LOAEL of 4.6 mg/kg bw/d could therefore be defined. This LOAEL could be regarded as exposure level that gives information on intrinsic toxic properties of the substance. It would yet not be useful for DNEL derivation as the subcutaneous exposure route is not regarded as relevant for real-life exposure.

However, this LOAEL is eventually disregarded, adapting to the official opinion of MAK (1996) where the data of Gibel et al. (1974/1975) were disqualified. MAK evaluated the data quality to be questionable. In the study report of "Study on the oral toxicity of 3-methylbutanol-1 in rats - Administration via the drinking water over 3 months", Project No.: 33S0056/88020, performed by BASF (1990) and owned by BG RCI, was also referred to Gibel et al. (1974/1975). In the report is pointed out that the suspicion of carcinogenicity cannot be ruled out under consideration of the information in Gibel et al. (1974/1975) and that carcinogenity studies may therefore follow in the future. The German MAK Commission evaluated the data apparently different.

General justification for the use of read-across data of 3-methyl-1-butanol to isopentyl acetate:

Based on the available and adequate data on the metabolism of isopentyl acetate in the body (see under 7.1 Toxicokinetics, metabolism and distribution) it can be assumed that the ingestion of a certain amount of isopentyl acetate would lead to an equal molar amount of 3-methyl-1-butanol and acetic acid.
Acetic acid is not regarded as toxicologically relelevant compared to 3-methyl-1-butanol. Repeated dose effects of isopentyl acetate should therefore be found to be the same or similar to the effects of 3-methyl-1-butanol. This study on 3-methyl-1-butanol is therefore regarded as meaningful for the description of repeated dose effects of isopentyl acetate.

All available and adequate data from repeated dose studies was generated by the use of 3-methyl-1-butanol as test substance, administered orally and in one study via subcutaneous route (data entered under IUCLID 7.5.1 + 7.5.4). These data should be regarded together in a weight of evidence approach to evaluate possible toxic effects from the repeated exposure to isopentyl acetate.