Ammonium chloride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data on ammonium chloride is present. However, reliable data available on diammonium hydrogenorthophosphate shows a NOAEL for reproductive toxicity after oral exposure of rats of ≥1500 mg/kg bw/day. Based on the toxicity profile, the properties of the NH4+ and chloride ions and the daily intake of chloride, the overall conclusion is that no additional studies are considered necessary.

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In aqueous solution, ammonium salts are completely dissociated into NH4+ and a corresponding anion. This equilibrium depends on temperature, pH and ionic strength of the water in the environment. Un-ionized NH3 species exists in the aquatic environments and the fraction (NH3/(NH3 +NH4+)) steeply increases with elevated pH value or temperature. It is well known that toxicity to aquatic organisms has been attributed to un-ionized ammonia (NH3) species, and NH4 + species is considered to be non- or significantly less-toxic (Emerson et al., 1975). However, recent developments in assessing ammonia toxicity clearly show that in contrast to earlier assumptions where un-ionized ammonia was considered to be the toxic component, both the uncharged and charged molecule are toxic. Therefore, a joint toxicity model has been proposed, with ammonia causing most toxicity at high pH values and ammonium ion also contributing to toxicity at lower pH values (U.S. EPA 1999, OECD 2007).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source substance: diammonium sulfate, CAS 7783-20-2
Target substance: ammonium chloride, CAS 12125-02-9

3. ANALOGUE APPROACH JUSTIFICATION
It is generally accepted, that the principal toxic component of ammonium salts such as ammonium chloride or -sulphate is ammonia, rather than the corresponding anion (see also: OECD 2004, SIDS ammonium chloride or OECD 2007 ammonium sulphate). Therefore toxicity values for ammonium salts (such as: ammonium -sulphates, phosphates, carbonates, chlorides or nitrates), where the major toxic component is ammonia, can be considered as equivalent. Consequently, this hazard assessment comprises the total topic of ammonia toxicity.

Reason / purpose for cross-reference:

read-across source

Reproductive effects observed:

no

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2001-12-28 to 2002-10-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

1996-03-22

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD (TM) (SD)IGS BR strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent England, UK
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: Males: 298 - 386 g; Females: 191 - 263 g
- Housing: individually in RB3 modified cages
- Diet: Rat and Mouse No. 1 Maintenance Diet (Special Diets Services Ltd., Witham, Essex, England, UK), ad libitum
- Water: tap water from public supply, ad libitum
- Acclimation period: 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 40 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2001-12-12 To: 2002-02-10 (necropsy)

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The formulation for Group 4 (150 mg/mL) was mixed by adding the required volume of vehicle (water purified by reverse osmosis) to the required weight of the test item and magnetically stirring for up to 1 hour until a visibly homogenous brown suspension was formed. Formulation for Groups 3 and 2 were prepared by direct dilution of this suspension.

VEHICLE
- Concentration in vehicle: 25 - 75 - 150 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: up to 2 weeks (although all animals were mated and were seperated within 1 week)
- Proof of pregnancy: sperm in vaginal smear or at least three copulation plugs referred to as day 0 of pregnancy
- No unsuccessful pairing occurred.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged: individually housed in RB3 solid-bottomed cages.
- Any other deviations from standard protocol: no.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of each formulation prepared for administration during Weeks 1, 4 and 6 of the study were analysed for test material content and found to be satisfactory.

Duration of treatment / exposure:

Exposure period: not clearly defined
Premating exposure period (males): 2 weeks
Premating exposure period (females): 2 weeks
Duration of test: not clearly defined
See freetext below

Frequency of treatment:

once daily

Details on study schedule:

- Age at mating of the reproductive subgroup animals: 11 - 12 weeks

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Dose / conc.:

750 mg/kg bw/day (actual dose received)

Dose / conc.:

1 500 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

5 males and 5 females per group (toxicity subgroups);
5 males and 10 females per group (reproductive subgroups)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: As no treatment-related effects were seen on parameters assessed in a preliminary study at 1000 mg/kg bw/day, the high dosage of 1500 mg/kg bw/day was selected by the Sponsor to attempt to elicit an overt toxic response and establish a reference level for toxicity. The concept of a 'Limit Dose' is accepted by the OECD and is generally set in the region of 1000 mg/kg bw/day; therefore, it was not considered necessary to investigate a dosage above 1500 mg/kg bw/day.

- Rationale for animal assignment: The animal numbers were assigned to groups in non-sequential manner due to the need for the functional observation battery and detailed clinical signs to be performed without knowledge of the treatment groups to which animals were assigned.

- Section schedule rationale: The sequence in which the animals of the toxicity subgroup were killed after completion of the observation period was selected to allow satisfactory inter-group comparison. Reproductive subgroup males were killed after the toxicity subgroup animals and reproductive subgroup females were killed on Day 4 of lactation.

Positive control:

No

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily
- Cage side observations: evidence of reaction to treatment or ill-health

DETAILED PHYSICAL OBSERVATIONS: Yes
- Time schedule: weekly
- A more detailed physical examination was performed on each animal by an observer. After removal from the home cage, animals were assessed for physical condition and behaviour during handling and after being placed in a standard arena. During these examinations particular attention was paid to possible signs of neurotoxicity such as convulsions, tremor and abnormalities of gait or behaviour.

ADDITIONAL DETAILED OBSERVATIONS: Yes
- Time schedule: during Week 1 daily according to the following frequency:
1. Pre-dose observation, 2.As each animal was returned to its home cage, 3.At the end of dosing each group, 4.Between 1 and 2 hours after completion of dosing all groups and 5.As late as possible in the working day. From Week 2 to termination daily observations were limited to 1 and 4.

BODY WEIGHT: Yes
- Time schedule for examinations: Each male and toxicity subgroup female: on the day that treatment commenced, weekly thereafter, and at necropsy. Reproductive subgroup females: on the first day of treatment, weekly until pairing and on Days 0, 7, 14, 17 and 20 after mating, and Days 1 and 4 of lactation, and at necropsy.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for observations: All males and toxicity subgroup females: weekly throughout the study with the exception of the males whilst in pairing with the reproductive subgroup females. Reproductive subgroup females: weekly before pairing then on Days 0,7,14, 17 and 20 after mating and Days 1 and 4 of lactation. No food consumption was recorded for toxicity subgroup males or reproductive subgroup animals during pairing.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OTHER:
Mating performance and fertility:
All 10 males in each group (toxicity and reproductive subgroups) were mated with the 10 reproductive subgroup females after all animals had received 2 weeks of treatment. Pairing was on a one-to-one basis within treatment groups for up to 2 weeks, although all animals mated and were separated within 1 week. Each morning, following pairing, the trays beneath the cages were checked for ejected copulation plugs and a wet vaginal smear was prepared from each female and examined for the presence of spermatozoa. The day on which a sperm positive vaginal smear or at least three copulation plugs were found was designated Day 0 of gestation. Once mating had been confirmed, males and females were separated and the males were returned to their normal group housing.

Parturition observations and gestation length:
From Day 20 after mating reproductive subgroup animals were checked 3 times daily for evidence of parturition. The females were permitted to deliver their young naturally and rear their own offspring until Day 4 of lactation. Numbers of live and dead offspring were recorded during the parturition process.

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: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: During week 5, following FOB examinations
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes, overnight
- How many animals: toxicity subgroup animals (5 males + 5 females per dose group)
- Parameters checked: Haematocrit (Hct), Haemoglobin (Hb), Red blood cell count (RBC), Mean cell haemoglobin (MCH), Mean cell haemoglobin concentration (MCHC), Mean cell volume (MCV), Total white cell count (WBC), Differential WBC count, Neutrophils (N), Lymphocytes (L), Eosinophils (E), Basophils (B), Monocytes (M), Large unstained cells (LUC), Platelet count (Pit), Reticulocyte count (Retic), Blood film for abnormal morphology and unusual cell types, including normoblasts (The most common morphological changes, anisocytosis (aniscyto), micro/macrocytosis (Microcyto/Macrocyto), hypo/hyperchromasia (Hypochrom/Hyperchrom), Platelet clumping (PIt. Clump)), Prothrombin time (PT) and Activated partial thromboplastin time (APTT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During week 5, following FOB examinations
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes, overnight
- How many animals: toxicity subgroup animals (5 males + 5 females per dose group)
- Parameters checked: Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyl transpeptidase (gGT), Total Bilirubin (Bili), Urea, Creatinine (Creat), Glucose (Gluc), Total cholesterol (Chol), Sodium (Na), Potassium (K), Chloride (Cl), Calcium (Ca), Inorganic Phosphorus (Phos), Magnesium (Mg), Total protein (Total Prot), Albumin (Alb), Albumin/globulin ratio (A/G Ratio)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: After 4 weeks of treatment
- Dose groups that were examined: Toxicity subgroup animals (5 males + 5 females per dose group)
- Battery of functions tested: Approach response, Touch response, Startle reflex (auditory), Tail pinch response, Grip strength: forelimb and hindlimb and motor activity.

Litter observations:

All offspring were examined at approximately 24 hours after birth (Day 1) and the number of offspring born (live and dead) was recorded. Live offspring were individually identified within each litter by toe tattoo and any clinical observations were recorded.
Litters were observed daily for evidence of abnormal appearance or behaviour. Daily records were maintained of mortality and consequent changes in litter size. Where practical, any offspring found dead were subjected to a macroscopic examination as soon as possible. The offspring were sexed at individual weighing on Day 1 and Day 4 of age.

Postmortem examinations (parental animals):

GROSS PATHOLOGY
Toxicity subgroup animals were sacrificed during week 6 of treatment. The following tissues were retained, weighed and examined:
adrenals, aorta, brain, caecum, colon, duodenum, epididymis, eyes, heart, ileum, jejunum, kidneys, liver, lungs including bronchi, lymph nodes (mandibular, mesenteric, regional to masses), mammary area, oesophagus, optic nerves, ovaries, pancreas, pituitary, prostrate, rectum, salivary glands, sciatic nerves, seminal vesicles, skin, spinal cord, spleen, sternum with bone marrow, stomach, testes, thymus, thyroid with parathyroid, trachea, urinary bladder, uterus with cervix, vagina.

Reproductive subgroup males were killed after the toxicity subgroup animals. The testes, epididymides, seminal vesicles with coagulating gland and prostate were retained for each animal. Reproductive subgroup females were killed on Day 4 of lactation. The number of implantation sites was recorded and the ovaries, uterus with oviducts and cervix, vagina, pituitary and mammary tissue retained. Abnormal tissues were also retained.

HISTOPATHOLOGY
The tissues mentioned above from control and high dose group animals of the toxicity subgroups were examined histopathologically. Histology for reproductive subgroup animals was restricted to the retained reproductive organs and abnormalities observed at macroscopic necropsy.

Postmortem examinations (offspring):

SACRIFICE
Offspring of were killed by intraperitoneal injection of sodium pentobarbitone on Day 4 of age and subjected to a macroscopic necropsy. Any offspring dying before scheduled termination were subjected to necropsy and assessment of the stomach for milk.

GROSS NECROPSY
Gross necropsy consisted of detailed examination of the external features and orifices, the neck and associated tissues and the cranial, thoracic, abdominal and pelvic cavities and their viscera. Abnormal tissues were also retained in appropriate fixative.

HISTOPATHOLOGY / ORGAN WEIGTHS
Abnormalities observed at macroscopic necropsy.

Statistics:

For some parameters, the similarity of the data was such that analyses were not considered to be necessary.
For categorical data, the proportion of animals was analysed using Fisher's Exact test.
For continuous data, Bartlett's test was first applied to test the homogeneity of variance between the groups. Using tests dependent on the outcome
of Bartlett's test, treated groups were then compared with the Control group, incorporating adjustment for multiple comparisons where necessary.
For bodyweight gains and organ weights, whenever Bartlett's test was found to be statistically significant, a Behrens-Fisher test was used to perform
pairwise comparisons, otherwise a Dunnett's test was used.
The following sequence of statistical tests was used for grip strength and motor activity, bodyweight change during gestation and lactation,
bodyweight and bodyweight change for offspring, food consumption and clinical pathology data:
- If 75% of the data were the same value, then a frequency analysis was applied. Treatment groups were compared using a Mantel test for a trend in
proportions and also pairwise Fisher's Exact tests for each dose group against the control.
- If Bartlett's test for variance homogeneity was not significant at the 1 % level, then parametric analysis was applied. If the F 1 test for monotonicity of dose-response was not significant at the 1 % level, Williams' test for a monotonic trend was applied. If the F 1 test was significant, Dunnett's test was
performed instead.
- If Bartlett's test was significant at the 1 % level, then logarithmic and square-root transformations were tried. If Bartlett's test was still significant, the non-parametric tests were applied. If the HI test for monotonicity of dose-response was not significant at the 1 % level, Shirley's test for a monotonic
trend was applied. If the HI test was significant, Steel's test was performed instead.

Significant differences were expressed at the 5% (p<0.05) or 1% (p<0.01) level.

Reproductive indices:

Percentage mating = 100 * (animals with evidence of mating) / (animals paired)
Conception rate = 100 * (animals achieving a pregnancy) / (animals with evidence of mating)
Fertility index = 100 * (animals achieving a pregnancy) / (animals paired)
Gestation index = 100 * (number of live litters born) / (number pregnant)

Offspring viability indices:

Post-implantation survival index = 100 * (total number of offspring born) / (total number of implantation sites)
Live birth index = 100 * (total number of offspring on Day 1 of littering) / (total number of offspring born)
Viability index = 100 * (total number of offspring on Day 4 of littering) / (total number of offspring on Day 1 of littering)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Treatment at all dosages was well tolerated and there were no treatment-related deaths.
A dosage dependent increase in transient post-dosing salivation was apparent, which was considered to be due to the palatability of the test formulations rather than toxicity. A dosage-dependent increase in the number of animals with reddening of the extremities was also apparent mainly during the early stages of treatment.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight gain and food consumption of males at 1500 mg/kg bw/day appeared to be suppressed when compared with the control group, such that gain between weeks 0 - 5 for this group was 78 % of controls. The body weight gain for reproductive subgroup females receiving 1500 mg/kg bw/day was reduced during the first week of gestation, after which the values returned to levels comparable with the control.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Mating performance and fertility were unaffected by treatment, and parental treatment had no apparent effect on the offspring to day 4 of age.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Relative kidney and liver weights for females at 1500 mg/kg bw/day were greater than in the control group, but there were no histological changes associated.

GROSS PATHOLOGY, HISTOPATHOLOGY (PARENTAL ANIMALS)
A number of treated animals at 750 and 1500 mg/kg bw/day exhibited horizontal banding on the incisors at necropsy; histological processing of these tissues failed to detect any change in the areas examined suggesting that the banding was restricted to the enamel of the teeth. The only histological findings related to treatment were the inflammatory/degenerative stomach changes in all treated groups that were considered likely to have arisen due to an irritant effect of the test formutations.

OTHER FINDINGS (PARENTAL ANIMALS)

HAEMATOLOGY, CLINICAL CHEMISTRY
Some treatment-related effects on hematology were evident (reduction in activated partial thromboplastin time for males at 750 and 1500 mg/kg bw/day, a non dosage-dependent elevation of alkaline phosphatase levels at 750 and 1500 mg/kg bw/day, reduced glucose and phosphorous levels at 1500 mg/kg bw/day, a dosage-dependent reduction in total protein at 750 and 1500 mg/kg bw/day with a slight elevated albumin/globulin ratio at the top dosage. Changes in females were limited to a decrease in phosphorous levels and a non-significant increase in alkaline phosphatase level at 1500 mg/kg bw).

BEHAVIOUR
There were no changes apparent at behavioral testing.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

> 1 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive parameters

Effect level:

> 1 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Critical effects observed:

no

Parental treatment had no apparent effect on the offspring to day 4 of age.

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Generation:

F1

Effect level:

> 1 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

not specified

Reference 3

Endpoint:

two-generation reproductive toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No reliable studies with ammonium chloride are present. In an OECD 422 study rats (10/sex/dose) were dosed with 250, 750 and 1500 mg/kg bw/day diammonium hydrogenorthophosphate orally via gavage. Males were treated until termination during week 6 of treatment. Doses were administered to the females for two weeks prior to pairing, throughout pairing and gestation until Day 3 of lactation. No effects on reproduction parameters were observed up to the highest dose tested. Therefore, the NOAEL is considered to be ≥1500 mg/kg bw/day.

In accordance with REACH Annex XI section 1, no further studies are considered necessary. Ammonium chloride dissociates into NH4+ and chloride ions. Chloride is needed for metabolisms in the human body and it also helps to keep the acid-base balance of the body. It also has several physiological roles in the central nervous system and biological transport proteins. The amount of chloride is controlled by the kidneys. The EPA Secondary Drinking Water Regulations recommend a maximum concentration of 250 mg/L for chloride ions. NH4+ ions are immediately transformed into urea by the liver and do not exist in the blood in relevant amounts unless in case of liver failure. Together with the available data showing no effects, an additional study is not considered necessary.

The available data from the OECD422 study show no effects on reproduction and developmental parameters in the presence of maternal toxic effects. The lack of effects at dose levels well in excess of the NOAEL based on general toxicity suggests that ammonium dihydrogenorthophosphate is not a significant risk to the reproductive process and further studies are unlikely to show any significant effects. Overall, an additional study is unlikely to result in providing further evidence of reproductive/developmental toxicity as the existing data have demonstrated a lack of effect at dose levels well in excess of general toxicity and expected human exposure. Therefore, such a study is not considered necessary.

Effects on developmental toxicity

Description of key information

No teratogenic effects were observed in three limited studies with rats (Goldman et al., 1964, Ellison et al., 1972 and Khera et al., 1991). Addtionally, experience with ammonium chloride used in humans for medication purposes does not indicate potential danger to the unborn child.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

There are no teratogenic studies available for ammonium chloride that meet current testing requirements. Available data is assessed in a weight of evidence approach.

In one study, 10 pregnant Sprague-Dawley rats were given an oral (unspecified) dose of 1/6 M ammonium chloride in saline (1 mL/ kg bw; 8.9 mg/kg bw/day) on days 7 to 10 of gestation. The foetuses were examined on day 20 of gestation. Dams exhibited metabolic acidosis. No teratogenic toxicity was found. Fetal growth retardation was seen, however this effect is considered to be incidental to maternal acidosis (Goldman et al 1964). In another study, 6.0 % ammonium chloride was administered in the diet to 10 gravid female rats (no data on strain) from day 9 - 12 of gestation. On day 20 of gestation, the animals were sacrificed, and the foetuses examined grossly for malformation. Skeletal malformation were also examined. Metabolic acidosis were seen in dams. Teratogenic toxicity was not evident (Ellison et al. 1972). Khera et al. (1991) also reported the absence of teratogenic effects, fetogenic effects as well as embryogenic affects in rats after the administration of ammonium chloride (421 mg/kg bw/d) via drinking water to 13 gravid Sprague-Dawley rats on days 7 -11 of gestation. The control animals received water.

Ammonium chloride dissociates into NH4+ and chlorine ions. Chloride ions are a normal body and nutritional component and are tightly regulated within the body. NH4+ ions are immediately transformed into urea by the liver and do not exist in the blood in relevant amounts unless in case of liver failure. The conduct of a study with a second species is thus not justified.

Experience with ammonium chloride used in humans for medication purposes does not indicate potential danger to the unborn child. In Australia, for example, ammonium chloride is a category A substance. Category A means that it is a medicine which has been used for many pregnant women and women of conceiving age, with no proof of increase in the frequency of deformation and the frequency of direct or indirect detrimental action to the embryo. In Japan, there is no restriction to medication to a pregnant woman (assessment SIDS, Ammonium Chloride 2004).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on toxicity to reproduction and developmental toxicity, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.