Registration Dossier

Administrative data

Description of key information

Based on the available data Guanidine hydrochloride is irritating to the skin and irritating to the eye.

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:
3 May 1984 - 5 Jun 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedure according to national (US) standard, deviations to international guidelines regarding integrity of treated skin, exposure duration
Qualifier:
according to
Guideline:
other: EPA TS-792 Dermal irritation. Health effects test guidelines, EPA, August 1982; EPA 560/6-82-001
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Elkhorn Rabbitry, 5265 Starr Way, Watsonville, CA 95076
- Age at study initiation: young adults
- Weight at study initiation: 3.1 to 3.6 kg
- Housing: individually
- Diet (e.g. ad libitum): 150 g of Certified Purina Chow Diet 5322
- Water (e.g. ad libitum): d libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.7 to 18.9°C
- Humidity (%): 40 to 70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
semiocclusive
Preparation of test site:
other: one test site shaved, one test site shaved+abraded
Vehicle:
physiological saline
Controls:
other: vehicle-treated sites on the same animals
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

VEHICLE
The test compound was moistened with a few drops physiological saline (0.9%) to make a thick paste.
Duration of treatment / exposure:
24 h
Observation period:
14 d
Number of animals:
6 (3 males, 3 females)
Details on study design:
TEST SITE
- Area of exposure: 2.5x2.5 cm
- Type of wrap if used: Blenderm (semi-impervious hypoallergenic surgical tape)

REMOVAL OF TEST SUBSTANCE
- Washing (if done):skin was wiped, if the material adhered
- Time after start of exposure: 24 h

SCORING SYSTEM: according to Draize scale
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean 24, 48, 72 h
Score:
1.67
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean 24, 48, 72 h
Score:
3.67
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: this animal has severe razor burns, thus should be regarded as abraded
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean 24, 48, 72 h
Score:
1.33
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
other: mean 24, 48, 72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
other: mean 24, 48, 72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
other: mean 24, 48, 72 h
Score:
2.67
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal: #1, #3, #5
Time point:
other: mean 24, 48, 72 h
Score:
0
Max. score:
4
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean 24, 48, 72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 2 d
Remarks on result:
other: this animal has severe razor burns, thus should be regarded as abraded
Irritation parameter:
edema score
Basis:
animal #4
Time point:
other: mean 24, 48, 72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 3 d
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #6
Time point:
other: mean 24, 48, 72 h
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 14 d
Remarks on result:
other: intact skin
Irritant / corrosive response data:
One rabbit was severely razor-burned during preclipping and still exhibited very slight erythema (score 1) at dosing. Consequently, the "non-abraded" sites were actually abraded and these sites exhibited necrosis and sloughling earlier than the non-abraded sites of the other animals. However, four of the remaining five rabbits possessed sites which exhibited necrosis and sloughing; therefore, the razor burns on this rabbit did not affect the overall final irritation rating of the compound.

Intact skin:
- erythema scores:
Erythema scores for the intact sites were first obtained after wrap removal (after 24 h of exposure). The erythema scores for this period ranged from slight (score 1) in one animal, to welldefined (score 2) in three animals, and to moderate-to-severe (score 3) in two animals. The scores remained the same or improved slightly through Day 7 for all except two animals, of which animal number 2 had severe razor burns. In this animal the application site had progressed
to necrosis by the second day, followed by eschar formation and sloughing within the first week.
During the second week, the test compound application site for three of the remaining four animals had also progressed to necrosis with eschar formation and sloughing.
- edema scores:
Edema at the intact sites was negligible. Three animals exhibited very slight edema formation (score 1). This had cleared by the third day after application in two animals and by Day 7 in the third rabbit.

Abraded skin:
The erythema at the abraded sites of all six animals were evaluated as moderate tn severe (score 3) when wraps were removed 24 h after application of the test compound. In four of the animals this had progressed to necrosis by the third day with eschar formation and sloughing developing within the first week. The application site on a fifth animal progressed to eschar formation during the second week.
Edema at the abraded sites was more prevalent and slightly more severe, but still reversible within 3 days.
Other effects:
none reported

Animal

Intact skin

Abraded skin

 

Erythema scores

Day 1/2/3/7/14

Edema scores

Day 1/2/3/7/14

Erythema scores

Day 1/2/3/7/14

Edema scores

Day 1/2/3/7/14

1

2/2/1/1/4

0/0/0/0/0

3/3/4/4/4

0/0/0/0/0

2*

3/4/4/4/4

1/0/0/0/0

3/4/4/4/4

2/0/0/0/0

3

2/1/1/2/4

0/0/0/0/0

3/4/4/4/4

1/0/0/2/0

4

3/3/3/3/4

0/1/0/0/0

3/3/3/3/4

1/1/0/0/0

5

1/1/1/1/1

0/0/0/0/0

3/4/4/4/4

2/1/0/0/0

6

2/3/3/3/3

1/1/0/1/0

3/3/3/3/3

2/0/0/0/0

* this animal has severe razor burns, thus should be regarded as abraded

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008)
Conclusions:
Guanidine hydrochloride is legally classified as irritating to the skin (CLP, EU GHS (Regulation (EC) No 1272/2008)).
Executive summary:

In a primary dermal irritation study according to EPA guideline 560/6-82-001 (Primary Dermal Irritation), August 1982, 6 young adult New Zealand White rabbits were dermally exposed to 0.5 mg of Guanidine hydrochloride (>98%) for 24 hours to 2.5 cm x 2.5 cm body surface area to intact and abraded skin using semi-occlusive dressing. Animals then were observed for 14 days. The scoring system was according to Draize.

On intact skin, erythema scores after 24 h ranged from slight (score 1) in one animal, to well-defined (score 2) in three animals, and to moderate-to-severe (score 3) in two animals. The scores remained the same or improved slightly through day 7 for all except two animals, of which one animal had severe razor burns. In this animal the application site had progressed to necrosis by the second day, followed by eschar formation and sloughing within the first week.

During the second week, the test compound application site for three of the remaining four animals had also progressed to necrosis with eschar formation and sloughing.

Edema at the intact sites was negligible. Three animals exhibited very slight edema formation (score 1). This had cleared by the third day after application in two animals and by Day 7 in the third rabbit.

The erythema at the abraded sites of all six animals were moderate to severe (grade 3) after 24 h. In four of the animals this had progressed to necrosis by the third day with eschar formation and sloughing developing within the first week. The application site on a fifth animal progressed to eschar formation during the second week. Edema at the abraded sites was more prevalent and slightly more severe, but still reversible within 3 days.

The irritation response on intact skin sites was not reversible within 14 days.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (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:
1984-05-03 to 1984-06-09
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions, Observation was not continued until fully reversibility, or 21 days.
Qualifier:
according to
Guideline:
other: EPA 560/6-82-001 (Primary Eye Irritation), August 1982
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Observation was not continued until fully reversibility, or 21 days.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Elkhorn Rabbitry, 5265 Starr Way, Watsonville, CA 95076
- Age at study initiation: young adults
- Weight at study initiation: 2.3 - 2.9 kg
- Housing: individually
- Diet (e.g. ad libitum): 150 g of Certified Purina Chow Diet 5322
- Water (e.g. ad libitum): d libitum
- Acclimation period: 14 d minimum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.1 to 20.0°C, except for a spike to 21.1°C during a steam outage
- Humidity (%): 40 to 70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated left eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL was recalculated to mg: 81.4 mg ± 1.0 mg

Duration of treatment / exposure:
no removal of the test substance
Observation period (in vivo):
14 d
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: fluorescein for scoring at 24 h, 7 and 14 d
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #5, #6
Time point:
other: mean 24, 48, 72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: mean 24, 48, 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 d
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: mean 24, 48, 72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 7 d
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
other: mean 24, 48, 72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
iris score
Basis:
animal: #1, #4, #5, #6
Time point:
other: mean 24, 48, 72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: mean 24, 48, 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 d
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: mean 24, 48, 72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: mean 24, 48, 72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 14 d
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: mean 24, 48, 72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 14 d
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: mean 24, 48, 72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 14 d
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
other: mean 24, 48, 72 h
Score:
1.67
Max. score:
3
Reversibility:
fully reversible within: 14 d
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
other: mean 24, 48, 72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 7 d
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
other: mean 24, 48, 72 h
Score:
1.67
Max. score:
3
Reversibility:
not fully reversible within: 14 d
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean 24, 48, 72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean 24, 48, 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: mean 24, 48, 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 d
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
other: mean 24, 48, 72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
other: mean 24, 48, 72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
other: mean 24, 48, 72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritant / corrosive response data:
- slight corneal opacity (grade 1) was observed in 3/6 rabbits for up to 4 days
- 2/6 animals showed slight iritis (vascular injection; grade 1) after 24 h, this was reversible after 48 h and 4 d, respectively
- slight to moderate conjunctival redness (grade 1 - 2) was observed in all animals, reversibility was achieved in 5/6 animals within 14 d
- in one animal slight redness (grade 1) was still present on day 14, but this can be judged as resolution of the initial lesion and can therefore expected to be reversible within 21 d
- slight to moderate chemosis (grade 1 - 2) was observed in all animals being fully reversible within 14 d

 Animal number  Cornea score1 h/ 1/2/3/4/7/14 d  Iris score 1 h/ 1/2/3/4/7/14 d  Conjunctival redness score 1 h/ 1/2/3/4/7/14 d  Conjuntival chemosis score 1 h/ 1/2/3/4/7/14 d
1  0/0/0/0/0/0/0  0/0/0/0/0/0/0  1/1/2/1/1/1/0  1/0/0/0/0/0/0
2  1/1/1/1/1/0/0  0/1/1/1/1/0/0  1/2/2/2/2/1/0  2/1/1/1/2/1/0
3  0/0/1/1/1/0/0  0/1/0/0/0/0/0 0/1/1/1/0/1/0   1/2/1/0/1/0/0
4  0/0/1/0/0/0/0  0/0/0/0/0/0/0  1/1/2/2/2/1/0 2/2/2/1/1/1/0
5  0/0/0/0/0/0/0  0/0/0/0/0/0/0  1/1/1/1/1/0/0  1/1/1/0/0/0/0
6  0/0/0/0/0/0/0  0/0/0/0/0/0/0  1/1/2/2/2/1/1  2/1/2/1/1/1/0
Interpretation of results:
irritating
Remarks:
Migrated information due to legally binding Classification & Labelling Criteria used for interpretation of results: other: CLP, EU GHS (Regulation (EC) No 1272/2008
Conclusions:
Guanidine hydrochloride is legally classified as irritating to the eye (CLP, EU GHS (Regulation (EC) No 1272/2008)).
Executive summary:

In a primary eye irritation study similar to OECD guideline 405, 81.4 ± 1.0 mg (corresponding to 0.1 mL) of Guanidine hydrochloride (98% purity) was instilled into the conjunctival sac of 6 male, young adult New Zealand White rabbits. The eyes were not rinsed. Animals then were observed for 14 days. Irritation was scored similar to OECD guideline 405, at 1, 4, 24, 48 and 72 hours and at 7, 14 and 21 days. At 24, 48, 72 hours as well as 7 and 14 days post application the eyes were further examined with fluorescein to look for cornea damage.

Slight corneal opacity (grade 1) was observed in 3/6 rabbits for up to 4 days. 2/6 animals showed slight iritis (vascular injection; grade 1) after 24 h, which was reversible within 4 d. Slight to moderate conjunctival redness (grade 1 - 2) was observed in all animals; reversibility was achieved in 5/6 animals within 14 d. In one animal slight redness (grade 1) was still present on day 14, but this was judged as resolution of the initial lesion by the study authors and can therefore be expected to be fully reversible within 21 d, although observation was not continued until full reversibility was achieved. Slight to moderate chemosis (grade 1 - 2) was observed in all animals being fully reversible within 14 d.

Guanidine hydrochloride is legally classified as irritating to the eye.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Reliable, relevant and adequate data on the skin and eye irritation of Guanidine hydrochloride are available:

In a primary dermal irritation study according to EPA guideline 560/6-82-001 (Primary Dermal Irritation), August 1982, 6 young adult New Zealand White rabbits were dermally exposed to 0.5 mg of Guanidine hydrochloride (>98%) for 24 hours to 2.5 cm x 2.5 cm body surface area to intact and abraded skin. Animals then were observed for 14 days. The scoring system is similar to OECD guideline 404.

On intact skin, erythema scores after 24 h ranged from slight (score 1) in one animal, to well-defined (score 2) in three animals, and to moderate-to-severe (score 3) in two animals. The scores remained the same or improved slightly through day 7 for all except two animals, of which one animal had severe razor burns. In this animal the application site had progressed to necrosis by the second day, followed by eschar formation and sloughing within the first week.

During the second week, the test compound application site for three of the remaining four animals had also progressed to necrosis with eschar formation and sloughing.

Edema at the intact sites was negligible. Three animals exhibited very slight edema formation (score 1). This had cleared by the third day after application in two animals and by Day 7 in the third rabbit.

The erythema at the abraded sites of all six animals were moderate to severe (grade 3) after 24 h. In four of the animals this had progressed to necrosis by the third day with eschar formation and sloughing developing within the first week. The application site on a fifth animal progressed to eschar formation during the second week. Edema at the abraded sites was more prevalent and slightly more severe, but still reversible within 3 days.

The irritation response on intact skin sites was not reversible within 14 days.

Guanidine hydrochloride is legally classified as irritating to the skin (CLP, EU GHS (Regulation (EC) No 1272/2008)).

In a primary eye irritation study similar to OECD guideline 405, 81.4 ± 1.0 mg (corresponding to 0.1 mL) of Guanidine hydrochloride (98% purity) was instilled into the conjunctival sac of 6 male, young adult New Zealand White rabbits. The eyes were not rinsed. Animals then were observed for 14 days. Irritation was scored similar to OECD guideline 405, at 1, 4, 24, 48 and 72 hours and at 7, 14 and 21 days. At 24, 48, 72 hours as well as 7 and 14 days post application the eyes were further examined with fluorescein to look for cornea damage.

Slight corneal opacity (grade 1) was observed in 3/6 rabbits for up to 4 days. 2/6 animals showed slight iritis (vascular injection; grade 1) after 24 h, which was reversible within 4 d. Slight to moderate conjunctival redness (grade 1 - 2) was observed in all animals; reversibility was achieved in 5/6 animals within 14 d. In one animal slight redness (grade 1) was still present on day 14, but this was judged as resolution of the initial lesion by the study authors and can therefore be expected to be fully reversible within 21 d, although observation was not continued until full reversibility was achieved. Slight to moderate chemosis (grade 1 - 2) was observed in all animals being fully reversible within 14 d.

Guanidine hydrochloride is legally classified as irritating to the eye.

Supporting data

Additional supporting data from the read-across substance guanidine nitrate were included to demonstrate the similar toxicological profile of both substances. Data were used to substantiate the justification for read-across, outlined in IUCLID chapter 13 of technical dossier and chapter 1.1.2 Justification for Read-across (Analogue approach) of CSR.


Justification for selection of skin irritation / corrosion endpoint:
Only one key study available

Justification for selection of eye irritation endpoint:
Only one key study available

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

According to CLP, EU GHS (Regulation (EC) No 1272/2008), Guanidine hydrochloride is classified as irritating to the eye and skin and has to be labelled with H315 “Causes skin irritation” and H319 "Causes serious eye irritation".

According to Directive 67/548 EEC Guanidine hydrochloride is classified as irritating to the eye and skin and has to be labelled with R36/38 "Irritating to eyes and skin".