Heptanoic anhydride

Endpoint summary

Description of key information

Skin irritation (rat): not irritating [Kurth 2006]
Eye irritation (rabbit): not irritating [Amir 2005]

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug 2002 to Feb 2003

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

- exposure time 24 hrs instead of 4 hrs, few details in test description and reporting

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Tierzucht Schönwalde GmbH, Schönwalde, Germany
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 276-313 g (males), 188-193 g (females)
- Housing: 1 animal per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: >= 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-23°C
- Humidity (%): 54-62 %
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

unchanged (no vehicle)

Controls:

other: the untreated skin served as control

Amount / concentration applied:

0.64-0.67 mL / male animal or 0.40 -0.42 mL / female animal (= 2000 mg/kg bw)

Duration of treatment / exposure:

24 hours

Observation period:

14 days

Number of animals:

3 males and 3 females

Details on study design:

Skin areas were assessed 1, 24, 48 and 72 hours after the end of administration. Evaluation of skin reactions(reddening, scab formation and swelling of the skin) was done according to the system recommended in Directive 67/548/EEC.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.95

Max. score:

4

Reversibility:

fully reversible within: 11 days

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Very slight to slight skin reddening was noted in all animals treated with 2000 mg/kg bw. In addition, desquamation was observed in all female animals and in two male animals. The local intolerance reactions observed in rats were reversible within 11 days after administration. The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0 for swelling and 0.95 for reddening and scab formation (see table 1).

Table 1: Mean values of findings relevant for classification.

Test compound ZK 56406 (2000 gm/kg)		Animal number and sex
Location (finding)	Time-point after end of exposure	10M	11M	12M	4F	5F	6F
Reddening and scab formation	1 hour*	0	0	2	2	2	2
	24/25 hours	1	0	1	2	2	2
	48 hours	1	0	1	2	1	1
	72 hours	0	0	1	1	1	0
Individual mean values:		0.67	0	1.0	1.67	1.33	1.0
Mean value of all animals:							0.95
Swellings	1 hour*	0	0	0	0	0	0
	24/48 hours	0	0	0	0	0	0
	48 hours	0	0	0	0	0	0
	72 hours	0	0	0	0	0	0
Individual mean values:		0	0	0	0	0	0
Mean values of all animals:							0

M = male

F = female

*         = not included in calculations of mean values

Interpretation of results:

other: slight local intolerance reactions noted up to day 8.

Executive summary:

A single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg (0.64-0.67 mL / male or 0.40 -0.42 mL / female) led to slight local intolerance reactions up to day 8 after administration. The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0 for swelling and 0.95 for reddening and scab formation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug to Sep 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

- 4 instead of 3 animals

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River, Kisslegg, Germany
- Weight at study initiation: 2.7-2.9 kg (males), 2.6 kg (females)
- Housing: 1 animal per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: >= 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22°C
- Humidity (%): 56-62 %
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: the left eye, which remained untreated, served as control.

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

test substance remained in the eye (eye was not rinsed)

Observation period (in vivo):

10 days

Number of animals or in vitro replicates:

2 males and 2 females

Details on study design:

0.1 mL correspond to ca. 93 mg test substance

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 10 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 8 days

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 10 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 8 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

2

Reversibility:

fully reversible within: 3 days

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 8 days

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 8 days

Table 1: Results of the study

		Irritant effects (score)
Animal no. (sex)	Irritation parameter	24 h	48 h	72 h	Mean scores
1 (M)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	1	1	1	1.0
	Conjunctiva (swelling)	1	1	1	1.0
2 (M)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	1	1	1	1.0
	Conjunctiva (swelling)	1	1	1	1.0
3 (F)	Cornea	0	0	0	0.0
	Iris	1	0	0	0.33
	Conjunctiva (reddening)	1	1	1	1.0
	Conjunctiva (swelling)	2	2	1	1.67
4 (F)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	1	1	1	1.0
	Conjunctiva (swelling)	1	1	1	1.0

The control eyes were without findings.

The single application of 0.1 mL ZK 56406 into the conjunctival sac of the right eye led to slight to moderate reddening and swelling of the conjunctivae in most of the animals from administration day one up to day 6. In one female animal reddening was seen up to day 7 and in one male animal up to day 9, respectively. In one male and in one female animal swelling of the conjunctivae appeared up to day 7 of the test. Vessel injection of the iris was seen in one female animal 24 hours after instillation. All animals were without findings on day 10.

Interpretation of results:

other: slight to moderate irritation (fully reversible by day 10)

Executive summary:

In a local tolerance test on the rabbit eye according to OECD TG 405 a single application of the test substance into the conjunctival sac provoked slight to moderate irritation on the day of administration which decreased in severity from day 2 onwards and were fully reversible on day 10 after administration. The mean values of findings relevant for classification at the time-points 24, 48 and 72 hours after application were 0 for the parameter cornea, 0.08 for iris, 1.17 for conjunctival swelling and 1.0 for conjunctival reddening. According to EU classification criteria ZK 56406 need not be labelled as an eye irritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A combined study on acute dermal toxicity and on local tolerance was conducted (Kurth, 2006). The study design and reporting deviates from the current OECD TG 404, however, the study was considered sufficient for assessment of skin irritation/corrosion. In this study a single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg (0.64-0.67 mL / male or 0.40 -0.42 mL / female) led to slight local intolerance reactions up to day 8 after administration. The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0 for swelling and 0.95 for reddening and scab formation according to the system recommended in Directive 67/548/EEC.

In addition, a single dermal administration of 0.25 mL ZK 56406 for up to 4 hours to female rabbits revealed slight to moderate local intolerance reactions in form of erythema, swelling, desquamation and wrinkling. In no case necrosis were observed (Schöbel, 1982).

In a local tolerance test on the rabbit eye according to OECD TG 405 a single application of the test substance into the conjunctival sac provoked slight to moderate irritation on the day of administration which decreased in severity from day 2 onwards and were fully reversible on day 10 after administration (Amir, 2005). The mean values of findings relevant for classification at the time-points 24, 48 and 72 hours after application were 0 for the parameter cornea, 0.08 for iris, 1.17 for conjunctival swelling and 1.0 for conjunctival reddening. According to EU classification criteria ZK 56406 need not be labelled as an eye irritant.

Justification for classification or non-classification

Based on the study results a classification according to Regulation (EC) No. 1272/2008 (CLP) is not required.